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1.  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.
PMCID: PMC2974792  PMID: 19446898
Amyloid; Heart failure; Microvascular dysfunction; Oxidative stress; Reactive oxygen species; Cardiomyopathy
2.  Prognostic implication of late gadolinium enhancement on cardiac MRI in light chain (AL) amyloidosis on long term follow up 
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.
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.
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).
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.
PMCID: PMC2686669  PMID: 19416541
3.  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.
PMCID: PMC2582214  PMID: 17935867
echocardiography; cardiomyopathy; heart failure; ventricular function; apoptosis
4.  Intraventricular dyssynchrony in light chain amyloidosis: a new mechanism of systolic dysfunction assessed by 3-dimensional echocardiography 
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.
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.
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.
Light chain amyloidosis is associated with left ventricular regional systolic dyssynchrony. Regional dyssynchrony may be an unrecognized mechanism of heart failure in AL subjects.
PMCID: PMC2525629  PMID: 18687125
5.  Myocardial dysfunction in the periinfarct and remote regions following anterior infarction in rats quantified by 2D radial strain echocardiography: An observational cohort study 
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.
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.
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).
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.
PMCID: PMC2397379  PMID: 18445286

Results 1-5 (5)