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1.  Monosialoganglioside‐Containing Nanoliposomes Restore Endothelial Function Impaired by AL Amyloidosis Light Chain Proteins 
Background
Light chain amyloidosis (AL) is associated with high mortality, especially in patients with advanced cardiovascular involvement. It is caused by toxicity of misfolded light chain proteins (LC) in vascular, cardiac, and other tissues. There is no treatment to reverse LC tissue toxicity. We tested the hypothesis that nanoliposomes composed of monosialoganglioside, phosphatidylcholine, and cholesterol (GM1 ganglioside–containing nanoliposomes [NLGM1]) can protect against LC‐induced human microvascular dysfunction and assess mechanisms behind the protective effect.
Methods and Results
The dilator responses of ex vivo abdominal adipose arterioles from human participants without AL to acetylcholine and papaverine were measured before and after exposure to LC (20 μg/mL) with or without NLGM1 (1:10 ratio for LC:NLGM1 mass). Human umbilical vein endothelial cells were exposed for 18 to 20 hours to vehicle, LC with or without NLGM1, or NLGM1 and compared for oxidative and nitrative stress response and cellular viability. LC impaired arteriole dilator response to acetylcholine, which was restored by co‐treatment with NLGM1. LC decreased endothelial cell nitric oxide production and cell viability while increasing superoxide and peroxynitrite; these adverse effects were reversed by NLGM1. NLGM1 increased endothelial cell protein expression of antioxidant enzymes heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 and increased nuclear factor, erythroid 2 like 2 (Nrf‐2) protein. Nrf‐2 gene knockdown reduced antioxidant stress response and reversed the protective effects of NLGM1.
Conclusions
NLGM1 protects against LC‐induced human microvascular endothelial dysfunction through increased nitric oxide bioavailability and reduced oxidative and nitrative stress mediated by Nrf‐2–dependent antioxidant stress response. These findings point to a potential novel therapeutic approach for light chain amyloidosis.
doi:10.1161/JAHA.116.003318
PMCID: PMC4937272  PMID: 27412900
amyloid; endothelium; nanotechnology; oxidant stress; Endothelium/Vascular Type/Nitric Oxide
2.  Clinical and Imaging Predictors of 1-year and Long-Term Mortality in Light Chain (AL) Amyloidosis: A 5-Year Follow Up Study 
Heart and vessels  2013;29(6):793-800.
Light chain amyloidosis (AL) involves multiorgan failure induced by amyloidogenic light chain proteins and is associated with high mortality. We aim to identify clinical, laboratory and imaging parameters that would predict 1-year and long-term AL mortality. 44 biopsy-proven AL patients (61.5±12 years, 20 females) underwent clinical evaluation including laboratory assays, echocardiography and contrast cardiac magnetic resonance imaging (CMR, n=31) prior to chemotherapy. Patients were prospectively followed for median duration of 62.7 months (IQR 35.5 months). Clinical and laboratory parameters were compared between 1-year survivors versus non-survivors. Univariate Kaplan-Meier survival plots were calculated followed by stepwise logistic regression analysis to assess independent predictors of long-term survival. Eighteen (40.9%) patients died within 1 year and an additional 10 subjects died during long-term follow up. Patients who expired within 1 year presented with more advanced heart failure class, higher alkaline phosphatase and uric acid, lower limb lead voltage on electrocardiography, shorter left ventricular ejection time (ET) on echocardiography and had higher proportion of late gadolinium enhancement (LGE) on CMR. On multivariable analysis, only ET≤240 ms on echocardiography (HR 5.07, 95% CI 1.83–14.1, p=0.002) and NYHA functional class II–IV presentation (HR 1.0058, 95% CI 1.0014–1.0103, p=0.01) were independent predictors of AL mortality. In conclusion, AL amyloidosis is associated with high 1-year and long-term mortality. Among clinical, laboratory and imaging parameters tested, echocardiographic finding of ET≤240 ms has independent and additive prognostic value to clinical heart failure evaluation in determining long-term survival of AL patients. This may be important in early identification of at-risk patients.
doi:10.1007/s00380-013-0419-x
PMCID: PMC3992190  PMID: 24141988
amyloid; heart failure; echocardiography; cardiac magnetic resonance
3.  Machine learning to predict rapid progression of carotid atherosclerosis in patients with impaired glucose tolerance 
Objectives
Prediabetes is a major epidemic and is associated with adverse cardio-cerebrovascular outcomes. Early identification of patients who will develop rapid progression of atherosclerosis could be beneficial for improved risk stratification. In this paper, we investigate important factors impacting the prediction, using several machine learning methods, of rapid progression of carotid intima-media thickness in impaired glucose tolerance (IGT) participants.
Methods
In the Actos Now for Prevention of Diabetes (ACT NOW) study, 382 participants with IGT underwent carotid intima-media thickness (CIMT) ultrasound evaluation at baseline and at 15–18 months, and were divided into rapid progressors (RP, n = 39, 58 ± 17.5 μM change) and non-rapid progressors (NRP, n = 343, 5.8 ± 20 μM change, p < 0.001 versus RP). To deal with complex multi-modal data consisting of demographic, clinical, and laboratory variables, we propose a general data-driven framework to investigate the ACT NOW dataset. In particular, we first employed a Fisher Score-based feature selection method to identify the most effective variables and then proposed a probabilistic Bayes-based learning method for the prediction. Comparison of the methods and factors was conducted using area under the receiver operating characteristic curve (AUC) analyses and Brier score.
Results
The experimental results show that the proposed learning methods performed well in identifying or predicting RP. Among the methods, the performance of Naïve Bayes was the best (AUC 0.797, Brier score 0.085) compared to multilayer perceptron (0.729, 0.086) and random forest (0.642, 0.10). The results also show that feature selection has a significant positive impact on the data prediction performance.
Conclusions
By dealing with multi-modal data, the proposed learning methods show effectiveness in predicting prediabetics at risk for rapid atherosclerosis progression. The proposed framework demonstrated utility in outcome prediction in a typical multidimensional clinical dataset with a relatively small number of subjects, extending the potential utility of machine learning approaches beyond extremely large-scale datasets.
doi:10.1186/s13637-016-0049-6
PMCID: PMC5011483  PMID: 27642290
Machine learning; Atherosclerosis; Diabetes; Prognosis; Model
4.  Exenatide Protects Against Glucose- and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans 
Diabetes  2015;64(7):2624-2635.
GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The current study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonist–mediated vasodilation. Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, and glucose and lipid responses to breakfast and lunch were determined; and 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells. Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF, and exendin-9 abolished this effect. Exenatide elicited eNOS activation and NO production in endothelial cells, and induced dose-dependent vasorelaxation and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo. These effects were reduced with AMPK inhibition. In conclusion, exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid-induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMPK activation.
doi:10.2337/db14-0976
PMCID: PMC4477348  PMID: 25720388
5.  Left Ventricular Ejection Time on Echocardiography Predicts Long-Term Mortality in Light Chain Amyloidosis 
Light chain amyloidosis (AL) is associated with high mortality. The aim was to identify echocardiographic parameters that predict AL long-term mortality.
Methods/Results
42 biopsy-proven AL subjects (43% females; 61±12 years) had echocardiography and followed 29±16 (median 29.4) months. Standard echocardiographic and clinical parameters and heart failure (HF) class were tested using univariate/multivariable Cox proportional hazard regression analyses to identify markers of mortality. 23 subjects died with 1-year mortality of 44%. Univariate predictors of mortality were HF class (p<0.001), left ventricular systolic ejection time (ET, p=0.002), alkaline phosphatase (p<0.001), aspartate and alanine aminotransferase (p=0.003 each). On multivariable analysis, only HF Class (hazards ratio, 95% confidence interval, p-value: 4.86, 1.58-14.9, p=0.006), ET (10 ms increase, 0.87, 0.78-0.97, p=0.01) and alkaline phosphatase (10 U/L increase, 1.04, 1.01-1.06, p=0.01) were prognostic. ET≤240 ms had sensitivity/specificity of 61/90% in predicting 1-year mortality and 73/90% in predicting 1-year cardiac mortality.
Conclusions
AL amyloidosis was associated with high long-term mortality. Among echocardiographic and clinical parameters, only ET and alkaline phosphatase had incremental value to HF class in predicting mortality. This may be useful to identify high-risk patients.
doi:10.1016/j.echo.2009.09.012
PMCID: PMC2787973  PMID: 19880277
6.  Usefulness of Two-Dimensional Strain Echocardiography to Predict Segmental Viability Following Acute Myocardial Infarction and Optimization Using Bayesian Logistic Spatial Modeling 
The American journal of cardiology  2009;104(8):1023-1029.
Viability assessment following acute myocardial infarction (MI) is important to guide revascularization. Two-dimensional strain echocardiography (2DSE) was shown to predict viability but the methodology assumed strain in each segment is independent of contiguous segments. We tested the hypotheses that segmental strain post-MI are spatially correlated and that using Bayesian approach improves prediction of non-viable myocardium. 21 subjects (58±12 years, 6 females) with ≥2 weeks MI underwent 2DSE and late gadolinium enhancement (LGE) cardiac magnetic resonance imaging within 48-hours of each other. The heart was divided into 16 segments and longitudinal, radial and circumferential strains were measured using software. Using similar segmentation, LGE was measured and segments with >50% LGE were considered nonviable. Spearman analyses assessed spatial correlation of strain and receiver operating characteristic curve analysis was used to determine prediction of non-viable myocardium without and with Bayesian logistic spatial conditionally autoregressive (CAR) model. There is significant spatial correlation in strain and LGE, especially in the apex. Longitudinal strain was the best predictor of non-viability and was impaired in non-viable myocardium (-12.1±0.6, -8.0±0.6 and -4.6±1% for 0, 1-50, >50% LGE, respectively, p<0.001). Use of CAR model improved the area under the curve for detection of non-viable myocardium (0.7 to 0.94). A CAR probabilistic score of 0.17 had 88% sensitivity and 86% specificity for detecting non-viable myocardium. In conclusion, longitudinal strain from 2DSE can predict myocardial viability following MI and exploiting spatial correlations in segmental strain using Bayesian CAR enhances the ability of 2D strain to predict non-viable myocardium.
doi:10.1016/j.amjcard.2009.05.049
PMCID: PMC2856659  PMID: 19801018
myocardial infarction; strain echocardiography; viability; Bayesian analysis
7.  Adipose and leptomeningeal arteriole endothelial dysfunction induced by β-amyloid peptide: a practical human model to study Alzheimer's disease vasculopathy 
Background
Evidence point to vascular dysfunction and hypoperfusion as early abnormalities in Alzheimer's disease (AD); probing their mechanistic bases can lead to new therapeutic approaches. We tested the hypotheses that β-amyloid peptide induces endothelial dysfunction and oxidative stress in human microvasculature and that response will be similar between peripheral adipose and brain leptomeningeal arterioles.
New Method
Abdominal subcutaneous arterioles from living human subjects (n=17) and cadaver leptomeningeal arterioles (n=6) from rapid autopsy were exposed to Aβ1-42 (Aβ) for 1-hour and dilation response to acetylcholine/papaverine were measured and compared to baseline response. Adipose arteriole reactive oxygen species (ROS) production and nitrotyrosine content were measured.
Comparison with existing methods
Methods described allow direct investigation of human microvessel functional response that cannot be replicated by human noninvasive imaging or post-mortem histology.
Results
Adipose arterioles exposed to 2 μM Aβ showed impaired dilation to acetylcholine that was reversed by antioxidant polyethylene glycol superoxide dismutase (PEG-SOD) (Aβ-60.9±6%, control-93.2±1.8%, Aβ+PEGSOD-84.7±3.9%, both p<0.05 vs. Aβ). Aβ caused reduced dilation to papaverine. Aβ increased adipose arteriole ROS production and increased arteriole nitrotyrosine content. Leptomeningeal arterioles showed similar impaired response to acetylcholine when exposed to Aβ (43.0±6.2% versus 81.1±5.7% control, p<0.05).
Conclusion
Aβ exposure induced adipose arteriole endothelial and non-endothelial dysfunction and oxidative stress that were reversed by antioxidant treatment. Aβ-induced endothelial dysfunction was similar between peripheral adipose and leptomeningeal arterioles. Ex vivo living adipose and cadaver leptomeningeal arterioles are viable, novel and practical human tissue models to study Alzheimer's vascular pathophysiology.
doi:10.1016/j.jneumeth.2014.06.014
PMCID: PMC4175686  PMID: 25004204
Alzheimer's disease; amyloid; endothelial function; microvessels
8.  Early Detection of Doxorubicin Cardiomyopathy Using 2-Dimensional Strain Echocardiography 
Ultrasound in medicine & biology  2007;34(2):208-214.
Doxorubicin is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiomyopathy that may lead to heart failure. Conventional measures of ventricular function, such as fractional shortening, are insensitive in detecting early doxorubicin cardiomyopathy. We tested whether novel 2-dimensional radial strain echocardiography (2DSE) can detect early doxorubicin injury following chronic administration in a rat model. 14 male Sprague Dawley rats (240−260 g) received doxorubicin 2.5 mg/k IV per week for 10 (n=4) or 12 weeks (n=10); 17 controls received saline (10 weeks, n=7 and 12 weeks, n=10). Serial 2DSE from 0−12 weeks was done at the mid left ventricle using Vivid 7 echo (General Electric, Waukesha, WI, USA). With Q analysis software, radial strain was obtained. From the 2D image, anatomical M-mode through the anterior/inferior walls was used to measure fractional shortening. Fibrosis (Masson's trichrome) and caspase-3 activity were measured from excised hearts. Radial strain was lower in the doxorubicin group (12 week: 26.7±3 vs. 38.3±2.6%, p=0.006), with significant difference by 8 weeks whereas fractional shortening was lower with doxorubicin only after 12 weeks (30.2±1.7 vs. 37.6±1.4%, p=0.02). Doxorubicin group had lower cardiac mass (0.85±0.09 vs. 1.14±0.04 g, p=0.001), higher caspase-3 activity (1.95±0.2 fold increase over control, p<0.0001) and fibrosis (3.9±0.7 vs. 0.7±0.1%, p=0.005). Radial strain was related directly to cardiac mass (R=0.61, p=0.0007) and inversely to caspase-3 activity (R=−0.5, p=0.005). 2-dimensional radial strain echocardiography is useful in the early detection of doxorubicin cardiac injury and the reduction in radial strain is associated with histologic markers of doxorubicin cardiomyopathy.
doi:10.1016/j.ultrasmedbio.2007.07.018
PMCID: PMC2582214  PMID: 17935867
echocardiography; cardiomyopathy; heart failure; ventricular function; apoptosis
9.  Simvastatin mitigates increases in risk factors for and the occurrence of cardiac disease following 10 Gy total body irradiation 
The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20–120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.
doi:10.1002/prp2.145
PMCID: PMC4492761  PMID: 26171225
blood lipids; cardiovascular risk factors; coronary sclerosis; simvastatin; total body irradiation; ventricular function
10.  Cardiac injury following 10 Gy total body irradiation: indirect role of effects on abdominal organs 
Radiation research  2013;180(3):247-258.
The objective of this study was to determine whether radiation-induced injury to the heart after 10 Gy total body irradiation (TBI) is direct or indirect. Young male WAG/RijCmcr rats received a 10 Gy single dose using TBI, upper hemi-body (UHB) irradiation, lower hemi-body (LHB) irradiation, TBI with the kidneys shielded, or LHB irradiation with the intestines shielded. Age-matched, sham-irradiated rats served as controls. The lipid profile, kidney injury, heart and liver morphology and cardiac function were determined up to 120 days after irradiation. LHB, but not UHB irradiation, increased the risk factors for cardiac disease as well as the occurrence of cardiac and kidney injury in a way that was quantitatively and qualitatively similar to that observed after TBI. Shielding of the kidneys prevented the increases in risk factors for cardiac disease. Shielding of the intestines did not prevent the increases in risk factors for cardiac disease. There was no histological evidence of liver injury 120 days after irradiation. Injury to the heart from irradiation appears to be indirect, supporting the notion that injury to abdominal organs, principally the kidneys, is responsible for the increased risk factors for and the occurrence of cardiac disease after TBI and LHB irradiation.
doi:10.1667/RR3292.1
PMCID: PMC4042860  PMID: 23919311
blood lipids; total body irradiation; partial body irradiation; morphology; cardiac risk factors; heart disease
11.  Protective role of clusterin in preserving endothelial function in AL amyloidosis 
Atherosclerosis  2012;225(1):220-223.
Misfolded immunoglobulin light chain proteins (LC) in light chain amyloidosis (AL) are toxic to vascular tissues. We tested the hypothesis that chaperone protein clusterin preserves endothelial function and cell survival during LC exposure.
Methods
LC (20 μg/mL) were given to human aortic endothelial cells (EC) for 24-hours and clusterin protein/gene expression and secretion were measured. DNA fragmentation was measured with/without recombinant clusterin (Clu, 300 ng/mL). Adipose arterioles (non-AL subjects) were tested for dilator responses to acetylcholine/papaverine at baseline and after 1-hour of LC±Clu.
Results
LC reduced EC clusterin secretion, protein and gene expression while increasing DNA fragmentation. Clu attenuated LC-induced DNA fragmentation and restored dilator response to acetylcholine (logEC50: control −7.05±0.2, LC+Clu −6.53±0.4, LC −4.28±0.7, p<0.05 vs. control, LC+Clu).
Conclusions
LC induced endothelial cell death and dysfunction while reducing clusterin protein/gene expression and secretion. Exogenous clusterin attenuated LC toxicity. This represents a new pathobiologic mechanism and therapeutic target for AL amyloidosis.
doi:10.1016/j.atherosclerosis.2012.08.028
PMCID: PMC3478430  PMID: 22981431
amyloid; endothelial function; chaperone protein
13.  Systemic and microvascular oxidative stress induced by light chain amyloidosis 
Light chain amyloidosis (AL) is a plasma cell dyscrasia associated with production of amyloidogenic immunoglobulin light chains (LC). Despite its often fatal course, the mechanism of injury remains unknown. We tested the hypothesis that AL is associated with oxidative stress by comparing serum protein carbonyl (a marker of protein oxidation and oxidative stress) in AL subjects (n=23, 60±11 years) vs. controls (n=9, 54± 2 years); we also measured superoxide production (n=11) and dilator response to sodium nitroprusside (SNP, n=6) in isolated non-AL human adipose arterioles exposed to LC (20 μg/mL) purified from AL subjects for 1 h vs. control. Protein carbonyl was higher in AL patients (0.19±0.04 vs. 0.003±0.003 nmol/mg control, p=0.002). Post-exposure to LC proteins, arteriole superoxide was higher (1.89±0.36 times control, p=0.03) with impaired dilation to SNP (10−4 M, 54±6 vs. 86±4%, p=0.01, logEC50 −3.7±0.2 vs. −6.7±0.6, p=0.002). AL is associated with systemic oxidative stress and brief acute exposure to AL light chain proteins induces oxidative stress and microvascular dysfunction in human adipose arterioles. This novel mechanism of injury may be important in AL pathophysiology.
doi:10.1016/j.ijcard.2009.04.044
PMCID: PMC2974792  PMID: 19446898
Amyloid; Heart failure; Microvascular dysfunction; Oxidative stress; Reactive oxygen species; Cardiomyopathy
14.  Speckle-Tracking 2-Dimensional Strain Echocardiography: A New Noninvasive Imaging Tool to Evaluate Acute Rejection in Cardiac Transplantation 
Background
There remains no reliable noninvasive method to detect cardiac transplant rejection. Recently, speckle-tracking 2-dimensional strain echocardiography was shown to be sensitive in early detection of myocardial dysfunction in various models of cardiomyopathy. We aim to determine if 2DSE derived functional indices can detect cardiac transplant rejection.
Methods
Heterotopic rat cardiac transplantation was performed in histocompatible, isografts (ISO) or histoincompatible allografts (ALLO). Histological rejection scores were determined. Short-axis, mid-left ventricular (LV) echocardiography was performed on post-transplant day 6. Conventional measures of function such as LV fractional shortening and ejection fraction as well as 2-dimensional strain echocardiography parameters were measured.
Results
Despite class IIIB rejection in ALLO and no rejection in ISO, there was no difference in fractional shortening or ejection fraction (ISO vs. ALLO: 15±3 vs. 12±3%; 36±5 vs. 26±6%, respectively, both not significant). In contrast, 2DSE revealed decreases in global radial strain (ISO vs. ALLO: 12.6±5.6 vs. 1.1±0.2 %, P<0.05), peak radial systolic strain rate (ISO vs. ALLO: 3.10±0.74 vs. 0.54±0.13 s−1, P<0.001) and peak circumferential systolic strain rate (ISO vs. ALLO: −1.99±0.55 vs. −0.43±0.11 s−1, P<0.01).
Conclusions
Systolic strain imaging using 2-dimensional strain echocardiography differentiates myocardial function between experimental cardiac transplant rejection in ALLO and non-rejection in ISO. 2-dimensional strain echocardiography may be useful in early noninvasive detection of transplant rejection.
doi:10.1016/j.healun.2010.04.009
PMCID: PMC2926230  PMID: 20488730
15.  Carotid plaque regression following 6-month statin therapy assessed by 3T cardiovascular magnetic resonance: comparison with ultrasound intima media thickness 
Background
Cardiovascular magnetic resonance (CMR) allows volumetric carotid plaque measurement that has advantage over 2-dimensional ultrasound (US) intima-media thickness (IMT) in evaluating treatment response. We tested the hypothesis that 6-month statin treatment in patients with carotid plaque will lead to plaque regression when measured by 3 Tesla CMR but not by IMT.
Methods
Twenty-six subjects (67 ± 2 years, 7 females) with known carotid plaque (> 1.1 mm) and coronary or cerebrovascular atherosclerotic disease underwent 3T CMR (T1, T2, proton density and time of flight sequences) and US at baseline and following 6 months of statin therapy (6 had initiation, 7 had increase and 13 had maintenance of statin dosing). CMR plaque volume (PV) was measured in the region 12 mm below and up to 12 mm above carotid flow divider using software. Mean posterior IMT in the same region was measured. Baseline and 6-month CMR PV and US IMT were compared. Change in lipid rich/necrotic core (LR/NC) and calcification plaque components from CMR were related to change in PV.
Results
Low-density lipoprotein cholesterol decreased (86 ± 6 to 74 ± 4 mg/dL, p = 0.046). CMR PV decreased 5.8 ± 2% (1036 ± 59 to 976 ± 65 mm3, p = 0.018). Mean IMT was unchanged (1.12 ± 0.06 vs. 1.14 ± 0.06 mm, p = NS). Patients with initiation or increase of statins had -8.8 ± 2.8% PV change (p = 0.001) while patients with maintenance of statin dosing had -2.7 ± 3% change in PV (p = NS). There was circumferential heterogeneity in CMR plaque thickness with greatest thickness in the posterior carotid artery, in the region opposite the flow divider. Similarly there was circumferential regional difference in change of plaque thickness with significant plaque regression in the anterior carotid region in region of the flow divider. Change in LR/NC (R = 0.62, p = 0.006) and calcification (R = 0.45, p = 0.03) correlated with PV change.
Conclusions
Six month statin therapy in patients with carotid plaque led to reduced plaque volume by 3T CMR, but ultrasound posterior IMT did not show any change. The heterogeneous spatial distribution of plaque and regional differences in magnitude of plaque regression may explain the difference in findings and support volumetric measurement of plaque. 3T CMR has potential advantage over ultrasound IMT to assess treatment response in individuals and may allow reduced sample size, duration and cost of clinical trials of plaque regression.
doi:10.1186/1532-429X-13-37
PMCID: PMC3166901  PMID: 21812992
16.  10 GY TOTAL BODY IRRADIATION INCREASES RISK OF CORONARY SCLEROSIS, DEGENERATION OF HEART STRUCTURE AND FUNCTION IN A RAT MODEL 
Purpose
To determine the impact of 10 Gy total body irradiation (TBI) or local thorax irradiation, a dose relevant to a radiological terrorist threat, on lipid and liver profile, coronary microvasculature and ventricular function.
Materials and methods
WAG/RijCmcr rats received 10 Gy TBI followed by bone marrow transplantation, or 10 Gy local thorax irradiation. Age-matched, non-irradiated rats served as controls. The lipid profile and liver enzymes, coronary vessel morphology, nitric oxide synthase (NOS) isoforms, protease activated receptor (PAR)-1 expression and fibrinogen levels were compared. Two dimensional strain echocardiography assessed global radial and circumferential strain on the heart.
Results
TBI resulted in a sustained increase in total and low density lipoprotein (LDL) cholesterol (190±8 vs. 58±6; 82±8 vs. 13±3 mg/dL, respectively). The density of small coronary arterioles was decreased by 32%. Histology revealed complete blockage of some vessels while cardiomyocytes remained normal. TBI resulted in cellular peri-arterial fibrosis whereas control hearts had symmetrical penetrating vessels with less collagen and fibroblasts. TBI resulted in a 32±4% and 28±3% decrease in endothelial NOS and inducible NOS protein respectively, and a 21±4% and 35±5% increase in fibrinogen and PAR-1 protein respectively, after 120 days. TBI reduced radial strain (19±8 vs. 46±7%) and circumferential strain (-8±3 vs. −15±3%) compared to controls. Thorax-only irradiation produced no changes over the same time frame.
Conclusions
TBI with 10 Gy, a dose relevant to radiological terrorist threats, worsened lipid profile, injured coronary microvasculature, altered endothelial physiology and myocardial mechanics. These changes were not manifest with local thorax irradiation. Non-thoracic circulating factors may be promoting radiation-induced injury to the heart.
doi:10.3109/09553000903264473
PMCID: PMC2792125  PMID: 19995235
vascular sclerosis; blood lipids; ventricular function; total body irradiation; thorax only irradiation; morphology; cardiovascular risk factors
17.  Intravascular detection of inflamed atherosclerotic plaques using a fluorescent photosensitizer targeted to the scavenger receptor 
Inflammation plays an important role in the pathophysiology of atherosclerotic disease. We have previously shown that the targeted photosensitizer chlorin (e6) conjugated with maleylated albumin (MA-ce6) is taken up by macrophages via the scavenger receptor with high selectivity. In a rabbit model of inflamed plaque in New Zealand white rabbits via balloon injury of the aorto-iliac arteries and high cholesterol diet we showed that the targeted conjugate showed specificity towards plaques compared to free ce6. We now show that an intravascular fiber-based spectrofluorimeter advanced along the -iliac vessel through blood detects 24-fold higher fluorescence in atherosclerotic vessels compared to control rabbits (p < 0.001 ANOVA). Within the same animals, signal derived from the injured iliac artery was 16-fold higher than the contralateral uninjured iliac (p < 0.001). Arteries were removed and selective accumulation of MA-ce6 in plaques was confirmed using: (1) surface spectrofluorimetry, (2) fluorescence extraction of ce6 from aortic segments, and (3) confocal microscopy. Immunohistochemical analysis of the specimens showed a significant correlation between MA-ce6 uptake and RAM-11 macrophage staining (R = 0.83, p < 0.001) and an inverse correlation between MA-ce6 uptake and smooth muscle cell staining (R=−0.74, p < 0.001). MA-ce6 may function as a molecular imaging agent to detect and/or photodynamically treat inflamed plaques.
doi:10.1039/b710746c
PMCID: PMC2813573  PMID: 18167594
18.  Prognostic implication of late gadolinium enhancement on cardiac MRI in light chain (AL) amyloidosis on long term follow up 
Background
Light chain amyloidosis (AL) is a rare plasma cell dyscrasia associated with poor survival especially in the setting of heart failure. Late gadolinium enhancement (LGE) on cardiac MRI was recently found to correlate with myocardial amyloid deposition but the prognostic role is not established. The aim is to determine the prognostic significance of LGE in AL by comparing long term survival of AL patients with and without LGE.
Methods
Twenty nine consecutive patients (14 females; 62 ± 11 years) with biopsy-proven AL undergoing cardiac MRI with gadolinium as part of AL workup were included. Survival was prospectively followed 29 months (median) following MRI and compared between those with and without LGE by Kaplan-Meier and log-rank analyses.
Results
LGE was positive in 23 subjects (79%) and negative in 6 (21%). Left ventricular ejection fraction was 66 ± 17% in LGE-positive and 69 ± 12% in LGE-negative patients (p = 0.8). Overall 1-year mortality was 36%. On follow-up, 14/23 LGE-positive and none of LGE-negative patients died (log rank p = 0.0061). Presenting New York Heart Association heart failure class was also associated with poor survival (p = 0.0059). Survival between two LGE groups stratified by heart failure class still showed a significant difference by a stratified log-rank test (p = 0.04).
Conclusion
Late gadolinium enhancement is common and is associated with poor long-term survival in light chain amyloidosis, even after adjustment for heart failure class presentation. The prognostic significance of late gadolinium enhancement in this disease may be useful in patient risk-stratification.
doi:10.1186/1756-6649-9-5
PMCID: PMC2686669  PMID: 19416541
19.  Left atrial volume measurement with automated border detection by 3-dimensional echocardiography: comparison with magnetic resonance imaging 
Objective
Left atrial size is an important marker for adverse cardiovascular events. There is general consensus that left atrial volume index (LAVI) is the best measurement of size. The current LAVI measurement techniques are laborious. Semi-automated measurement with a 3-dimensional echocardiography (3DE) system may be a practical clinical alternative to measure LAVI, but it has not been adequately evaluated against Magnetic Resonance Imaging (MRI) gold standard. The aim of this study was to compare the accuracy of a commercially available 3D algorithm for measurement of LAVI against LAVI obtained from MRI and Area Length Method (ALM).
Design
In 27 consecutive subjects referred for cardiac MRI (age 54 ± 13 years, 63% male), LAVI was measured using 3 imaging modalities: 3DE, ALM, MRI and the results were correlated. ALM was measured using standard American Society of Echocardiography guidelines. The time required to measure LAVI by 3DE and ALM were compared.
Results
There was a significant correlation in systolic and diastolic LA volumes and left atrial ejection fraction between 3DE and MRI (r = 0.86 for systole, r = 0.76 for diastole, r = 0.88 for ejection fraction, P < 0.0001 for all). There was also significant correlation of diastolic volumes between 3DE and ALM (r = 0.77, P < 0.0001). The time to obtain LAVI was shorter using 3DE versus ALM (56 ± 8 vs 135 ± 55 seconds, P < 0.0001).
Conclusion
Three-dimensional echocardiography with semiautomatic border detection is a practical alternative for obtaining the left atrial volume in a time-efficient manner compared to the current standard.
doi:10.1186/1476-7120-7-16
PMCID: PMC2669050  PMID: 19335908
20.  Intraventricular dyssynchrony in light chain amyloidosis: a new mechanism of systolic dysfunction assessed by 3-dimensional echocardiography 
Background
Light chain amyloidosis (AL) is a rare but often fatal disease due to intractable heart failure. Amyloid deposition leads to diastolic dysfunction and often preserved ejection fraction. We hypothesize that AL is associated with regional systolic dyssynchrony. The aim is to compare left ventricular (LV) regional synchrony in AL subjects versus healthy controls using 16-segment dyssynchrony index measured from 3-dimension-al (3D) echocardiography.
Methods
Cardiac 3D echocardiography full volumes were acquired in 10 biopsy-proven AL subjects (60 ± 3 years, 5 females) and 10 healthy controls (52 ± 1 years, 5 females). The LV was subdivided into 16 segments and the time from end-diastole to the minimal systolic volume for each of the 16 segments was expressed as a percent of the cycle length. The standard deviations of these times provided a 16-segment dyssynchrony index (16-SD%). 16-SD% was compared between healthy and AL subjects.
Results
Left ventricular ejection fraction was comparable (control vs. AL: 62.4 ± 0.6 vs. 58.6 ± 2.8%, p = NS). 16-SD% was significantly higher in AL versus healthy subjects (5.93 ± 4.4 vs. 1.67 ± 0.87%, p = 0.003). 16-SD% correlated with left ventricular mass index (R 0.45, p = 0.04) but not to left ventricular ejection fraction.
Conclusion
Light chain amyloidosis is associated with left ventricular regional systolic dyssynchrony. Regional dyssynchrony may be an unrecognized mechanism of heart failure in AL subjects.
doi:10.1186/1476-7120-6-40
PMCID: PMC2525629  PMID: 18687125
21.  Myocardial dysfunction in the periinfarct and remote regions following anterior infarction in rats quantified by 2D radial strain echocardiography: An observational cohort study 
Background
Heart failure from adverse ventricular remodeling follows myocardial infarction, but the contribution of periinfarct and remote myocardium to the development of cardiomyopathy remains poorly defined. 2D strain echocardiography (2DSE) is a novel and sensitive tool to measure regional myocardial mechanics. The aim is to quantify radial strain in infarcted (I), periinfarct (PI) and remote (R) myocardial regions acutely and chronically following anterior infarction in rats.
Methods
The left anterior coronary artery of male Sprague-Dawley rats (270–370 g) were occluded for 20–30 minutes and 2DSE was performed in the acute setting (n = 10; baseline and 60 minutes post-reperfusion) and in the chronic setting (n = 14; baseline, 1, 3 and 6 weeks). Using software, radial strain was measured in the mid-ventricle in short axis view. The ventricle was divided into 3 regions: I (anteroseptum, anterior and anterolateral), PI – (inferoseptum and inferolateral) and R – (inferior). Infarct size was measured using triphenyl tetrazolium chloride in the acute group.
Results
Following infarct, adverse remodeling occurred with progressive increase in left ventricular size, mass and reduced fractional shortening within 6 weeks. Radial strain decreased not only in the infarct but also in the periinfarct and remote regions acutely and chronically (I, PI, R, change vs. baseline, 60 minutes -32.7 ± 8.7, -17.4 ± 9.4, -13.5 ± 11.6%; 6 weeks -24.4 ± 8.2, -17.7 ± 8.3, -15.2 ± 8.4% respectively, all p < 0.05). Reduced radial strain in periinfarct and remote regions occurred despite minimal or absent necrosis (area of necrosis I, PI, R: 48.8 ± 23, 5.1 ± 6.6, 0 ± 0%, p < 0.001 vs. I).
Conclusion
Following left anterior coronary occlusion, radial strain decreased at 60 minutes and up to 6 weeks in the periinfarct and remote regions, similar to the reduction in the infarct region. This demonstrates early and chronic myopathic process in periinfarct and remote regions following myocardial infarction that may be an under recognized but important contributor to adverse left ventricular remodeling and progression to ischemic cardiomyopathy.
doi:10.1186/1476-7120-6-17
PMCID: PMC2397379  PMID: 18445286
22.  High-Dose Folic Acid Acutely Improves Coronary Vasodilator Function in Patients With Coronary Artery Disease 
OBJECTIVES
We investigated the acute effect of orally administered high-dose folic acid on coronary dilator function in humans.
BACKGROUND
Folic acid and its active metabolite, 5-methyltetrahydrofolate, increase endothelium-dependent vasodilation in human peripheral circulation. However, the acute effect on coronary circulation is not known.
METHODS
Fourteen patients with ischemic heart disease, age 62 ± 12 years (mean ± SD), were enrolled in a double-blind, placebo-controlled crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) were determined by positron emission tomography, and myocardial flow reserve was calculated. Each patient was studied after ingestion of placebo and after ingestion of 30 mg folic acid. Myocardial zones were prospectively defined physiologically as “normal” versus “abnormal” on the basis of MBF response to adenosine 140 μg/kg/min (normal = MBF > 1.65 ml/min/g). Abnormal and normal zones were analyzed separately in a patient-based analysis.
RESULTS
Folate was associated with a reduction in mean arterial pressure (100 ± 12 mm Hg vs. 96 ± 11 mm Hg, placebo vs. folate, p < 0.03). Despite the fall in mean arterial pressure, folic acid significantly increased the MBF dose response to adenosine (p < 0.001 using analysis of variance) in abnormal zones, whereas MBF in normal zones did not change. In abnormal segments, folic acid increased peak MBF by 49% (1.45 ± 0.59 ml/min/g vs. 2.16 ± 1.01 ml/min/g, p < 0.02). Furthermore, folate increased dilator reserve by 83% in abnormal segments (0.77 ± 0.59 vs. ml/min/g 1.41 ± 1.08 ml/min/g, placebo vs. folate, p < 0.05), whereas dilator reserve in normal segments remained unchanged (2.00 ± 0.61 ml/min/g vs. 2.12 ± 0.69 ml/min/g, placebo vs. folate, p = NS).
CONCLUSIONS
The data demonstrate that high-dose oral folate acutely lowers blood pressure and enhances coronary dilation in patients with coronary artery disease.
doi:10.1016/j.jacc.2005.02.038
PMCID: PMC1255966  PMID: 15893170
Ado 140 = adenosine 140 μg/kg/min; MBF = myocardial blood flow; PET = positron emission tomography

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