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1.  Relation of N-Terminal Pro-B-Type Natriuretic Peptide With Diastolic Function in Hypertensive Heart Disease 
American Journal of Hypertension  2013;26(10):1234-1241.
BACKGROUND
Elevated natriuretic peptide levels in asymptomatic individuals without heart failure are associated with increased risk of adverse cardiovascular outcomes and may reflect subclinical cardiac dysfunction.
METHODS
In a sample of 313 asymptomatic individuals (51% women, mean age 61 years) with hypertension and diastolic dysfunction, we examined the association of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) with both conventional and advanced echocardiographic measures of systolic and diastolic function, including myocardial strain, using speckle-tracking–based analyses.
RESULTS
In univariate analyses, higher NT-proBNP was associated with greater left ventricular mass index (P = 0.003), left atrial volume index (P = 0.007), lateral E′ velocity (P < 0.0001), E/E′ ratio (P < 0.0001), peak global longitudinal systolic strain (P = 0.015), systolic strain rate (P = 0.021), and early diastolic strain rate (P < 0.0001). In multivariable analyses, NT-proBNP remained associated with measures of diastolic dysfunction, including lateral E′ velocity (P = 0.013) and the E/E′ ratio (P = 0.008). However, early diastolic strain rate was the echocardiographic parameter most strongly associated with NT-proBNP (P = 0.003).
CONCLUSIONS
In the setting of asymptomatic hypertensive heart disease and preserved ejection fraction, elevation in natriuretic peptide levels is predominantly associated with subclinical diastolic dysfunction.
doi:10.1093/ajh/hpt098
PMCID: PMC3773573  PMID: 23792241
blood pressure; diastolic function; hypertension; imaging; natriuretic peptides; speckle-tracking echocardiography; strain.
2.  Increasing Serum Soluble Angiotensin Converting Enzyme 2 Activity following Intensive Medical Therapy is Associated with Better Prognosis in Acute Decompensated Heart Failure 
Journal of cardiac failure  2013;19(9):605-610.
Background
Angiotensin-converting enzyme 2 (ACE2) is an endogenous counter-regulator of the renin-angiotensin system that has been recently identified in circulating form. We aim to investigate the relationship between changes in soluble ACE2 (sACE2) activity, myocardial performance and long-term clinical outcomes in patients with acute decompensated heart failure (ADHF). We hypothesize that increasing sACE2 activity levels during intensive medical treatment is associated with improved myocardial performance and long-term clinical outcomes.
Methods and Results
In 70 patients admitted to the intensive care unit with ADHF, serum sACE2 activity levels, echocardiographic data, and hemodynamic variables were collected within 12 hours of admission (n=70) and 48–72 hours following enrollment after intensive medical treatment (n=57). The median baseline and 48–72 hour serum sACE2 activity levels were 32 [23, 43] ng/mL and 40 [28, 60] ng/mL, respectively. Baseline serum sACE2 activity levels correlated with surrogate measures of right ventricular (RV) diastolic dysfunction, including right atrial volume index (RAVi) (r=0.31, p=0.010), tricuspid E/A ratio (r=0.39, p=0.007), as well as B-type natriuretic peptide (r=0.32, p=0.008). However, there were no correlations between serum sACE2 and left ventricular (LV) systolic or diastolic dysfunction. Following intensive medical therapy, a 50% increase in baseline serum sACE2 levels predicted a significant reduction in risk of death, cardiac transplantation, or ADHF re-hospitalization, including after adjustment for baseline age, RAVi, and BNP levels (Hazard ratio 0.35, 95% confidence interval 0.12–0.84, p=0.018).
Conclusion
In patients admitted with ADHF, increasing serum sACE2 activity levels during intensive medical therapy predict improved outcomes independent of underlying cardiac indices.
doi:10.1016/j.cardfail.2013.06.296
PMCID: PMC3781953  PMID: 24054336
Soluble angiotensin converting enzyme 2; acute decompensated heart failure; right ventricular diastolic dysfunction
3.  Fasting 2-Deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography to Detect Metabolic Changes in Pulmonary Arterial Hypertension Hearts over 1 Year 
Background: The development of tools to monitor the right ventricle in pulmonary arterial hypertension (PAH) is of clinical importance. PAH is associated with pathologic expression of the transcription factor hypoxia-inducible factor (HIF)-1α, which induces glycolytic metabolism and mobilization of proangiogenic progenitor (CD34+CD133+) cells. We hypothesized that PAH cardiac myocytes have a HIF-related switch to glycolytic metabolism that can be detected with fasting 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) and that glucose uptake is informative for cardiac function.
Methods: Six healthy control subjects and 14 patients with PAH underwent fasting FDG-PET and echocardiogram. Blood CD34+CD133+ cells and erythropoietin were measured as indicators of HIF activation. Twelve subjects in the PAH cohort underwent repeat studies 1 year later to determine if changes in FDG uptake were related to changes in echocardiographic parameters or to measures of HIF activation.
Measurements and Results: FDG uptake in the right ventricle was higher in patients with PAH than in healthy control subjects and correlated with echocardiographic measures of cardiac dysfunction and circulating CD34+CD133+ cells but not erythropoietin. Among patients with PAH, FDG uptake was lower in those receiving β-adrenergic receptor blockers. Changes in FDG uptake over time were related to changes in echocardiographic parameters and CD34+CD133+ cell numbers. Immunohistochemistry of explanted PAH hearts of patients undergoing transplantation revealed that HIF-1α was present in myocyte nuclei but was weakly detectable in control hearts.
Conclusions: PAH hearts have pathologic glycolytic metabolism that is quantitatively related to cardiac dysfunction over time, suggesting that metabolic imaging may be useful in therapeutic monitoring of patients.
doi:10.1513/AnnalsATS.201206-029OC
PMCID: PMC3960991  PMID: 23509326
hypoxia-inducible factor 1; alpha subunit; positron emission tomography; fluorodeoxyglucose F18; right ventricle; heart failure
4.  Effect of the Use and Timing of Bone Marrow Mononuclear Cell Delivery on Left Ventricular Function After Acute Myocardial Infarction: The TIME Randomized Trial 
Context
While the delivery of cell therapy following ST segment myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular (LV) function has not been analyzed in a trial that randomly designated the time of delivery.
Objective
To determine 1) the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery following STEMI on recovery of global and regional LV function and 2) if timing of BMC delivery (3 versus 7 days following reperfusion) influences this effect.
Design, Setting, and Patients
Between July 17, 2008 and November 15, 2011, 120 patients were enrolled in a randomized, 2×2 factorial, double-blind, placebo-controlled trial of the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) of patients with LV dysfunction (LV Ejection Fraction (LVEF) ≤45%) following successful primary percutaneous coronary intervention (PCI) of anterior STEMI.
Interventions
Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1 BMC:placebo) within 12 hours of aspiration and processing administered at Day 3 or Day 7 (randomized 1:1) post-PCI.
Main Outcome Measures
Co-primary endpoints were: 1) Change in global (LVEF) and regional (wall motion) LV function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and 2) Change in LV function as affected by timing of treatment on Day 3 versus Day 7. Secondary endpoints included major adverse cardiovascular events as well as changes in LV volumes and infarct size.
Results
Patient mean age was 56.9±10.9 years with 87.5% male. At 6 months, LVEF increased similarly in both BMC (45.2±10.6 to 48.3±13.3 %) and placebo groups (44.5±10.8 to 47.8±13.6 %). No detectable treatment effect on regional LV function was observed in either infarct or border zones. Differences between therapy groups in the change in global LV function over time when treated at Day 3 (−0.9±2.9%, 95% CI 6.6 to 4.9%, p=0.763) or Day 7 (1.1±2.9%, 95% CI −4.7 to 6.9, p=0.702) were not significant, nor were they different from each other. Also, timing of treatment had no detectable effect on recovery of regional LV function. Major adverse events were rare with no difference between groups.
Conclusions
Patients with STEMI, who underwent successful primary PCI and administration of intra-coronary BMCs at either 3 or 7 days following the event, had recovery of global and regional LV function similar to placebo
Trial Registration
ClinicalTrials.gov Number, NCT00684021
doi:10.1001/jama.2012.28726
PMCID: PMC3652242  PMID: 23129008
5.  Left ventricular strain distribution in healthy dogs and in dogs with tachycardia-induced dilated cardiomyopathy 
Background
Recently, left ventricular (LV) strain distribution pattern has been assessed in several cardiac disease states. Tachycardia-induced cardiomyopathy (TIC) is an animal model of non-ischemic cardiomyopathy well characterized in terms of global LV dysfunction but with poor understanding of regional variability in LV function. We hypothesized that TIC induces specific changes in LV strain distribution pattern.
Methods
Twenty five adult mongrel conscious dogs were trained to lie down calmly for echocardiography. In seven selected dogs, we implanted pacing system for TIC induction under general anesthesia. We measured LV geometry and function, strains, and torsion before and after the development of TIC in awake non-sedated state.
Results
In 25 healthy dogs, all three types of normal strain significantly increased from base to apex (p <0.05), while a definite and recognizable twist could be measured due to presence of shear strain. In 7 dogs with TIC, marked changes in LV mechanics occurred throughout the cardiac cycle, resulting in decrease of strain (p <0.001), twist (p <0.05), and negative peak twist rate (p <0.05). Interestingly, the relative decrease of strain due to TIC was more pronounced in the apex (p < 0.001), with the radial strain decreasing the most (p < 0.05).
Conclusion
TIC is accompanied by decreased systolic LV strain and twist deformation, as well as loss of early diastolic recoil. In addition, the decrease of strain was more profound in the apex. This “reverse” distribution of LV strain may help us understand LV dysfunction in the presence of nonischemic etiology.
doi:10.1186/1476-7120-11-43
PMCID: PMC4235052  PMID: 24304622
Strain echocardiography; Twist; Tachycardia induced cardiomyopathy
6.  Increased Exhaled Nitric Oxide Levels Following Exercise in Patients with Chronic Systolic Heart Failure with Pulmonary Venous Hypertension 
Journal of cardiac failure  2012;18(10):799-803.
Background
Fractional exhaled nitric oxide (eNO) is recognized as a marker of pulmonary endothelial function. Oxidative stress is associated to systemic endothelial nitric oxide production but its correlation with eNO in heart failure (HF) patients has not been described. Previous studies have reported increased eNO levels after exercise in symptomatic HF patients but decreased levels in pulmonary arterial hypertension. Our objective is to prospectively examine the potential myocardial and functional determinants of exercise-induced rise of eNO in HF.
Methods and Results
Thirty-four consecutive ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] ≤45%) underwent symptom-limited cardiopulmonary stress testing and echocardiography. eNO was determined immediately after exercise. Systemic endothelial dysfunction was assessed by asymmetric dimethylarginine (ADMA) and the L-arginine/ADMA ratio. In our study cohort (mean age 53 ±13 years, 76% male, median LVEF 31%, interquartile range [IQR]: 25 to 40), the mean eNO was 23 ±9 ppb. eNO levels were higher in patients with diastolic dysfunction stages 2 or 3 than stage 1 or normal diastology (26.1±9 vs. 19.5±7 ppb, p=0.013). eNO had a positive correlation with estimated systolic pulmonary artery pressure (r= 0.57; p=0.0009) and indexed left atrium volume (r= 0.43; p= 0.014), but did not correlate with cardiopulmonary exercise test parameters, ADMA, or symptom score.
Conclusions
In contrast to prior reports, the increase in post-exercise eNO observed in stable chronic systolic HF patients may be attributed to the presence of underlying pulmonary venous hypertension probably secondary to advanced diastolic dysfunction.
doi:10.1016/j.cardfail.2012.08.356
PMCID: PMC3466438  PMID: 23040116
Exhaled nitric oxide; congestive heart failure; pulmonary hypertension; echocardiography; asymmetric dimethylarginine
7.  European Corn Borer (Ostrinia nubilalis) Induced Responses Enhance Susceptibility in Maize 
PLoS ONE  2013;8(9):e73394.
Herbivore-induced plant responses have been widely described following attack on leaves; however, less attention has been paid to analogous local processes that occur in stems. Early studies of maize (Zea mays) responses to stem boring by European corn borer (ECB, Ostrinianubilalis) larvae revealed the presence of inducible acidic diterpenoid phytoalexins, termed kauralexins, and increases in the benzoxazinoid 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one-glucose (HDMBOA-Glc) after 24 h of herbivory. Despite these rapidly activated defenses, larval growth was not altered in short-term feeding assays. Unexpectedly, ECB growth significantly improved in assays using stem tissue preconditioned by 48 h of larval tunneling. Correspondingly, measures of total soluble protein increased over 2.6-fold in these challenged tissues and were accompanied by elevated levels of sucrose and free linoleic acid. While microarray analyses revealed up-regulation of over 1100 transcripts, fewer individual protein increases were demonstrable. Consistent with induced endoreduplication, both wounding and ECB stem attack resulted in similar significant expansion of the nucleus, nucleolus and levels of extractable DNA from challenged tissues. While many of these responses are triggered by wounding alone, biochemical changes further enhanced in response to ECB may be due to larval secreted effectors. Unlike other Lepidoptera examined, ECB excrete exceedingly high levels of the auxin indole-3-acetic acid (IAA) in their frass which is likely to contact and contaminate the surrounding feeding tunnel. Stem exposure to a metabolically stable auxin, such as 2,4-dichlorophenoxyacetic acid (2,4-D), promoted significant protein accumulation above wounding alone. As a future testable hypothesis, we propose that ECB-associated IAA may function as a candidate herbivore effector promoting the increased nutritional content of maize stems.
doi:10.1371/journal.pone.0073394
PMCID: PMC3759431  PMID: 24023868
8.  Open Access Integrated Therapeutic and Diagnostic Platforms for Personalized Cardiovascular Medicine  
Journal of Personalized Medicine  2013;3(3):203-237.
It is undeniable that the increasing costs in healthcare are a concern. Although technological advancements have been made in healthcare systems, the return on investment made by governments and payers has been poor. The current model of care is unsustainable and is due for an upgrade. In developed nations, a law of diminishing returns has been noted in population health standards, whilst in the developing world, westernized chronic illnesses, such as diabetes and cardiovascular disease have become emerging problems. The reasons for these trends are complex, multifactorial and not easily reversed. Personalized medicine has the potential to have a significant impact on these issues, but for it to be truly successful, interdisciplinary mass collaboration is required. We propose here a vision for open-access advanced analytics for personalized cardiac diagnostics using imaging, electrocardiography and genomics.
doi:10.3390/jpm3030203
PMCID: PMC4251391  PMID: 25562653
pharmacogenomics; echocardiography; electrocardiography; personalized medicine; genomics
9.  The Effects of Aging and Physical Activity on Doppler Measures of Diastolic Function 
The American journal of cardiology  2007;99(12):1629-1636.
Healthy aging results in changes in Doppler measures of diastolic function. It is unclear whether these alterations are a specific manifestation of the aging process or reflect a cardiac adaptation to a more sedentary lifestyle. It was hypothesized that healthy, but sedentary, aging would result in slowing of diastolic filling and myocardial relaxation, whereas lifelong endurance training would prevent such changes. Doppler data were measured in young subjects and sedentary and fit seniors across a broad range of loading conditions. Thirteen sedentary healthy (70 ± 4 years) and 12 fit Masters athlete (68 ± 3 years) seniors were recruited. Twelve young healthy (32 ± 9 years) subjects were used for comparison. Pulmonary capillary wedge pressure and Doppler variables were measured at the 6 loading conditions of baseline (twice), –15 and –30 mm Hg lower body negative pressure, and 2 levels of saline solution infusion. Doppler variables consisted of early and late mitral inflow velocity (E/A) ratio, isovolumetric relaxation time (IVRT), tissue Doppler velocities (TDI Emean), and propagation velocity of mitral inflow. Aging resulted in a decrease in E/A ratio (p <0.001), TDI Emean (p <0.001), and propagation velocity of mitral inflow (p <0.001) and an increase in IVRT (p = 0.001). Lifelong endurance training did not completely prevent the changes in E/A ratio (p = 0.212), IVRT (p = 0.546), or propagation velocity of mitral inflow (p = 1.00). Fit seniors were able to achieve E/A ratios of 1.0 during baseline and saline solution infusion. TDI Emean was higher in fit versus sedentary seniors at baseline (p = 0.012) and during maximal lower body negative pressure (p = 0.036), but not during saline solution infusion (p = 0.493). In conclusion, age-associated abnormalities in Doppler measures of myocardial filling and relaxation are only partially minimized by lifelong endurance training and therefore may be more specific to the aging process than secondary to years of deconditioning.
doi:10.1016/j.amjcard.2007.01.050
PMCID: PMC3716368  PMID: 17560865
10.  Characterization of Static and Dynamic Left Ventricular Diastolic Function in Patients With Heart Failure With a Preserved Ejection Fraction 
Circulation. Heart failure  2010;3(5):617-626.
Background
Congestive heart failure in the setting of a preserved left ventricular (LV) ejection fraction is increasing in prevalence among the senior population. The underlying pathophysiologic abnormalities in ventricular function and structure remain unclear for this disorder. We hypothesized that patients with heart failure with preserved ejection fraction (HFPEF) would have marked abnormalities in LV diastolic function with increased static diastolic stiffness and slowed myocardial relaxation compared with age-matched healthy controls.
Methods and Results
Eleven highly screened patients (4 men, 7 women) aged 73±7 years with HFPEF were recruited to participate in this study. Thirteen sedentary healthy controls (7 men, 6 women) aged 70±4 years also were recruited. All subjects underwent pulmonary artery catheterization with measurement of cardiac output, end-diastolic volumes, and pulmonary capillary wedge pressures at baseline; cardiac unloading (lower-body negative pressure or upright tilt); and cardiac loading (rapid saline infusion). The data were used to define the Frank-Starling and LV end-diastolic pressure-volume relationships. Doppler echocardiographic data (tissue Doppler velocities, isovolumic relaxation time, propagation velocity of early mitral inflow , E/A-wave ratio) were obtained at each level of cardiac preload. Compared with healthy controls, patients with HFPEF had similar LV contractile function and static LV compliance but reduced LV chamber distensibility with elevated filling pressures and slower myocardial relaxation as assessed by tissue Doppler imaging.
Conclusions
In this small, highly screened patient population with hemodynamically confirmed HFPEF, increased end-diastolic static ventricular stiffness relative to age-matched controls was not a universal finding. Nevertheless, patients with HFPEF, even when well compensated, had elevated filling pressures, reduced distensibility, and increased diastolic wall stress compared with controls. In contrast, LV relaxation as assessed by tissue Doppler variables appeared consistently impaired in patients with HFPEF.
doi:10.1161/CIRCHEARTFAILURE.109.867044
PMCID: PMC3716372  PMID: 20682947
heart failure; ventricular end-diastolic volume; aging; echocardiography Doppler; hemodynamics
11.  Ventricular Geometry, Strain, and Rotational Mechanics in Pulmonary Hypertension 
Circulation  2010;121(2):259-266.
Backgrounds
We tested the hypothesis that right ventricular (RV) pressure overload affects RV function, and further influences left ventricular (LV) geometry that adversely affects LV twist mechanics and segmental function.
Methods and Results
Echocardiographic images were prospectively acquired in 44 (46±12 years; 82%F) patients with evidence of pulmonary hypertension (PH) (estimated pulmonary systolic pressure [PASP] =71±23 mmHg) and in 44 age and gender-matched healthy subjects. Patients with intrinsic LV diseases were excluded. RV lateral wall (RVLAT) longitudinal strain (LS) and interventricular septal (IVS) LS were reduced in PH group compared with controls (-15.9±7.6% vs.-25.5±6.1%, p<0.001 and -17.3±4.4% vs.-20.2±3.9%, p=0.002, respectively), while LV lateral wall (LVLAT) LS was preserved. RVLAT and IVS LS, but not LVLAT LS, correlated with PASP(r=0.56, p<0.01; r=0.32, p<0.01) and LV eccentricity index (LVEI) (r=0.57, p<0.01; r=0.57, p<0.01). IVS and LVLAT circumferential strains (CS) were both reduced in the PH group. Although IVS CS and LVLAT CS correlated with PASP and LVEI, after adjusting CS for LVEI, differences between groups persisted for IVS CS (p<0.01) but not LVLAT CS (p=0.09). LV torsion was decreased in patients with PH compared with controls (9.6±4.9° vs. 14.7±4.9°, p<0.001). LV torsion inversely correlated with PASP (r=-0.39, p<0.01) and LVEI (r=-0.3, p<0.01). LV untwisting rates were similar in both groups (p=0.7).
Conclusions
Chronic RV pressure overload directly affects RV longitudinal systolic deformation. RV pressure overload further influences IVS and LV geometry, which impairs LV torsion and segmental LS and CS, more for the IVS than the free wall of the LV.
doi:10.1161/CIRCULATIONAHA.108.844340
PMCID: PMC2846516  PMID: 20048214
Torsion; pulmonary hypertension; strain; echocardiography
12.  Dysregulated Arginine Metabolism and Importance of Compensatory Dimethylarginine Dimethylaminohydrolase-1 in Pulmonary Hypertension Associated with Advanced Systolic Heart Failure 
Objective
To examine the hemodynamic determinants of dysregulated arginine metabolism in patients with acute decompensated heart failure and explore possible mechanism of arginine dysregulation in human heart failure.
Background
Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear.
Methods
We prospectively determined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and global arginine bioavailability ratio [GABR=arginine/(ornithine+citrulline)] by tandem mass spectrometry in subjects with advanced decompensated heart failure in the intensive care unit (“ADHF”, n=68) and with stable chronic heart failure (“CHF”, n=57).
Results
Compared to CHF subjects, plasma ADMA was significantly higher (median[interquartile range]: 1.29 [1.04–1.77] versus 0.87 [0.72–1.05] μM, p<0.0001), and GABR significantly lower (0.90 [0.69–1.22] versus 1.13 [0.92–1.37], p=0.002) in ADHF subjects. Elevated ADMA and diminished GABR were associated with higher systolic pulmonary artery pressure (sPAP) and higher central venous pressure, but not with other clinical or hemodynamic indices. We further observed myocardial levels of dimethylarginine dimethylaminohydrolase-1 (DDAH-1) were increased in CHF without elevated sPAP (<50mmHg), but diminished with elevated sPAP (≥50mmHg, difference with sPAP<50 mmHg, p=0.02).
Conclusions
Dysregulated arginine metabolism was observed in advanced decompensated heart failure, particularly with pulmonary hypertension and elevated intracardiac filling pressures. Compared to control hearts, we observed higher amounts of ADMA-degradation enzyme DDAH-1 (but similar amounts of ADMA-producing enzyme, PRMT-1) in the human failing myocardium.
doi:10.1016/j.jacc.2011.12.022
PMCID: PMC3565538  PMID: 22440215
Nitric oxide synthase; asymmetric dimethylarginine; heart failure; pulmonary hypertension
13.  Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Ischemic Heart Failure: The FOCUS-CCTRN Trial 
Context
Previous studies utilizing autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. The FOCUS protocol was designed to assess efficacy of a larger cell dose in an adequately well-powered phase II study.
Objective
To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular (LV) end systolic volume, or enhances maximal oxygen consumption in patients with coronary artery disease (CAD), LV dysfunction, and limiting heart failure and/or angina.
Design, Setting, and Patients
This is a 100 million cell, first-in-man randomized, double-blind, placebo-controlled trial was performed by the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) in symptomatic patients (NYHA II-III and/or CCS II-IV) receiving maximal medical therapy, with a left ventricular ejection fraction (LVEF)≤45%, perfusion defect by single-photon emission tomography (SPECT), and CAD not amenable to revascularization.
Intervention
All patients underwent bone marrow aspiration, isolation of BMCs using a standardized automated system performed locally, and transendocardial injection of 100 million BMCs or placebo (2:1 BMC: placebo).
Main Outcome Measures
Three co-primary endpoints assessed at 6 months were changes in (a) LV end systolic volume (LVESV) by echocardiography, (b) maximal oxygen consumption (MVO2), and (c) reversibility on SPECT. Secondary measures included other SPECT measures, magnetic resonance imaging (MRI), echocardiography, clinical improvement, and major adverse cardiac events (MACE). Phenotypic and functional analyses of the cell product were performed by the CCTRN Biorepository lab.
Results
Of 153 consented patients, a total of 92 (82 men; average age, 63 years) were randomized (n= 61 BMC, 31 placebo) at 5 sites between April 29, 2009 and April 18, 2011. Changes in LVESV index, (−0.9 ± 11.3 mL/m2; P = 0.733; 95% CI, −6.1 to 4.3), MVO2 (1.0 ± 2.9; P = 0.169; 95% CI, −0.42 to 2.34), percent reversible defect change, (−1.2 ± 23.3; P = 0.835; 95% CI, −12.50 to 10.12), and incidence of MACEwere not statistically significant. However, in an exploratory analysis the change in LVEF across the entire cohort by therapy group was significant (2.7 ± 5.2%; P = 0.030; 95% CI, 0.27 to 5.07).
Conclusions
This is the largest cell therapy trial of autologous BMCs in patients with ischemic LV dysfunction. In patients with chronic ischemic heart disease, transendocardial injection of BMCs compared to placebo did not improve LVESV, MVO2, or reversibility on SPECT.
doi:10.1001/jama.2012.418
PMCID: PMC3600947  PMID: 22447880
Chronic CAD; Ischemic Heart Failure; Chronic Angina; bone marrow mononuclear cells; cardiac performance
14.  Effect of Intracoronary Delivery of Autolologous Bone Marrow Mononuclear Cells Two to Three Weeks Following Acute Myocardial Infarction on Left-Ventricular Function: The LateTIME Randomized Trial 
Context
Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, since a substantial number of patients may not present for early cell delivery, we investigated the efficacy of autologous BMC delivery 2–3 weeks post-MI.
Objective
To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2–3 weeks following first MI.
Design, Setting, and Patients
LateTIME is a randomized, double-blind, placebo-controlled trial of the National Heart, Lung, and Blood Institute - sponsored Cardiovascular Cell Therapy Research Network (CCTRN) of 87 patients with significant LV dysfunction (LVEF ≤ 45%) following successful primary percutaneous coronary intervention (PCI).
Interventions
Intracoronary infusion of 150 × 106 autologous BMCs (total nucleated cells) or placebo (2:1 BMC:placebo) was performed within 12 hours of bone marrow aspiration after local automated cell processing.
Main Outcome Measures
The primary endpoints were changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone from baseline to 6 months as measured by cardiac MRI at a core lab blinded to treatment assignment Secondary endpoints included changes in LV volumes and infarct size.
Results
87 patients were randomized between July 2008 and February 2011: mean age = 57 ± 11 yrs, 83% male. Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible and safe. The change from baseline to six months in the BMC group, when compared to the placebo group, for LVEF (48.7 to 49.2% vs. 45.3 to 48.8%; Difference = −3.0, 95% CI −7.0 to 0.9), wall motion in the infarct zone (6.2 to 6.5 vs. 4.9 to 5.9 mm; Difference = −0.7, 95% CI −2.8 to 1.3), and wall motion in the border zone (16.0 to 16.6 mm vs. 16.1 to 19.3 mm; Difference = −2.6; 95% CI −6.0 to 0.8) were not statistically significant. There was no significant change in LV volumes and infarct volumes decreased by a similar amount in both groups at 6 months compared to baseline.
Conclusions
Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs compared to intracoronary placebo infusion, 2–3 weeks after PCI did not improve global or regional function at 6 months.
doi:10.1001/jama.2011.1670
PMCID: PMC3600981  PMID: 22084195
Acute myocardial infarction; bone marrow mononuclear cells; LVEF; cardiac MRI
15.  Intestinal ischemia following laparoscopic surgery: a case series 
Introduction
Intestinal ischemia is a rare complication of laparoscopic surgery. Its prognosis depends on a high index of suspicion and effective early treatment.
Case presentation
In the present report, we describe three cases where intestinal ischemia developed following laparoscopic surgery. Case 1 concerns a 52-year-old Caucasian man who developed large bowel ischemia following laparoscopic adjustable gastric band surgery. Case 2 concerns an 82-year-old Caucasian woman who developed fatal intestinal ischemia following laparoscopic cholecystectomy. Case 3 concerns a 58-year old Caucasian woman who developed right-sided lower intestinal ischemia following open cholecystectomy.
Conclusions
Intestinal ischemia is a rare complication of laparoscopic surgery. The identification of high-risk patients is an essential primary preventive measure. A high index of suspicion is required to make an early diagnosis, which may help improve outcomes.
doi:10.1186/1752-1947-7-25
PMCID: PMC3552963  PMID: 23336390
16.  Predictors of mitral annulus early diastolic velocity: impact of long-axis function, ventricular filling pattern, and relaxation 
Aims
Although left ventricular (LV) relaxation is well recognized as a predictor of mitral annulus (MA) early diastolic (E′) velocity, its significance relative to other predictors of E′ is less well understood.
Methods and results
We assessed 40 healthy volunteers, 43 patients with acutely decompensated chronic systolic heart failure (HF), and 36 patients with hypertrophic obstructive cardiomyopathy (HOCM) using echocardiography and right or left heart catheterization. Data were obtained at baseline. In addition, in healthy volunteers haemodynamics were varied by graded saline infusion and low body negative pressure, while in HF patients it was varied by vasoactive drug treatment. E- and A-wave velocity (E/A) ratio of the mitral valve inflow, systolic MA velocity integral (s′ integral) and E′ and late velocity (A′) of lateral and septal MA pulsed wave velocities were assessed by echocardiography. Time constant of isovolumic pressure decay τ0) was calculated from isovolumic relaxation time/[ln(aortic dicrotic notch pressure) – ln(LV filling pressure)]. In all three groups, s′ integral was the strongest predictor of E′ (partial r= 0.53–0.79; 0.81 for three groups combined), followed by E/A ratio (partial r= 0.10–0.78; 0.26 for all groups combined) and τ0 (partial r= −0.1 to 0.023; −0.21 for all groups combined).
Conclusion
In healthy adults, patients with systolic HF, or patients with HOCM, E′ is related to LV long-axis function and E/A ratio, a global marker of LV filling. E′ appears less sensitive to LV relaxation.
doi:10.1093/ejechocard/jer146
PMCID: PMC3216376  PMID: 21865226
Echocardiography; Relaxation; Tissue Doppler; Heart failure
18.  Echocardiographic Indices Do Not Reliably Track Changes in Left-Sided Filling Pressure in Healthy Subjects or Patients with Heart Failure with Preserved Ejection Fraction 
Background
In select patient populations, Doppler echocardiographic indices may be used to estimate left sided filling pressures. It is not known, however, whether changes in these indices track changes in left-sided filling pressures within individual healthy subjects or patients with heart failure with preserved ejection fraction (HFpEF). This knowledge is important as it would support, or refute, the serial use of these indices to estimate changes in filling pressures associated with the titration of medical therapy in patients with heart failure.
Methods and Results
Forty seven volunteers were enrolled: 11 highly screened elderly outpatients with a clear diagnosis of HFpEF, 24 healthy elderly subjects and 12 healthy young subjects. Each patient underwent right heart catheterization with simultaneous transthoracic echo. Pulmonary capillary wedge pressure (PCWP) and key echo indices (E/e’ & E/Vp) were measured at two baselines and during four preload altering maneuvers: lower body negative pressure (LBNP) -15 mmHg; LBNP -30 mmHg; rapid saline infusion of 10-15 ml/kg; and rapid saline infusion of 20-30 ml/kg. A random coefficient mixed model regression of PCWP vs. E/e’ and PCWP vs. E/Vp was performed for: 1) a composite of all data points; 2) a composite of all data points within each of the three groups. Linear regression analysis was performed for individual subjects. With this protocol, PCWP was manipulated from 0.8 to 28.8 mmHg. For E/e’, the composite random effects mixed model regression was PCWP = 0.58×E/e’+7.02 (p<0.001) confirming the weak but significant relationship between these two variables. Individual subject linear regression slopes (range: -6.76 to 11.03) and r2 (0.00 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. For E/Vp, the composite random coefficient mixed model regression was PCWP = 1.95×E/Vp +7.48 (p=0.005); once again, individual subject linear regression slopes (range: -16.42 to 25.39) and r2 (range: 0.02 to 0.94) were highly variable and often very different than those derived for the composite and group regressions.
Conclusions
Within individual subjects the non-invasive indices E/e’ and E/Vp do not reliably track changes in left-sided filling pressures as these pressures vary, precluding the use of these techniques in research studies with healthy volunteers or the titration of medical therapy in patients with HFpEF.
doi:10.1161/CIRCIMAGING.110.960575
PMCID: PMC3205913  PMID: 21788358
echocardiography; pressure; ultrasonics; Doppler; heart failure
19.  Usefulness of Plasma Galectin-3 Levels in Systolic Heart Failure to Predict Renal Insufficiency and Survival 
The American journal of cardiology  2011;108(3):385-390.
Galectin-3 plays an important role in fibroblast activation and fibrosis in animal models. Elevated galectin-3 levels are associated with poor long-term survival in heart failure (HF). We examined the relation between plasma galectin-3 levels and myocardial indices of systolic HF. We measured plasma galectin-3 in 133 chronic HF and 45 advanced decompensated HF subjects with echocardiographic and hemodynamic evaluation. In our chronic HF cohort, median plasma galectin-3 level was 13.9ng/mL [interquartile range: 12.1–16.9ng/mL]. Higher galectin-3 was associated with more advanced age (r=0.22, p=0.010) and poor renal function (estimated glomerular filtration rate [eGFR]: r= −0.24, p=0.007; cystatin C: r= 0.38, p<0.0001), and predicted all-cause mortality (Hazard ratio [HR] 1.86 [95% confidence interval: 1.36–2.54], p<0.001). In multivariate analysis, galectin-3 remained an independent predictor of all-cause mortality after adjusting for age, eGFR, left ventricular (LV) ejection fraction (EF), and mitral E/septal Ea (HR 1.94 [1.30–2.91], p=0.001). However, galectin-3 did not predict the combined endpoint of all-cause mortality, cardiac transplantation, or HF hospitalization (p>0.05). Furthermore, there were no relations between galectin-3 and LV end-diastolic volume index (r= −0.05, p=0.61), LVEF (r= 0.10, p=0.25), or LV diastolic function (mitral E/septal Ea: r= 0.06, p=0.52; left atrial volume index: r= 0.08, p=0.41). In our advanced decompensated HF cohort, we did not observe any relation between galectin-3 and echocardiographic or hemodynamic indices. In conclusion, high plasma galectin-3 levels were associated with renal insufficiency and poorer survival in patients with chronic systolic HF. However, we did not observe a relation between galectin-3 and echocardiographic or hemodynamic indices.
doi:10.1016/j.amjcard.2011.03.056
PMCID: PMC3137764  PMID: 21600537
Heart failure; galectin-3; renal function; prognosis
20.  SUBCLINICAL ECHOCARDIOGRAPHIC ABNORMALITIES IN PHENOTYPE-NEGATIVE CARRIERS OF MYBPC3 GENE MUTATION FOR HYERTROPHIC CARDIOMYOPATHY 
American heart journal  2011;162(2):262-267.e3.
Background
Early diastolic myocardial tissue Doppler (TD) velocities have reported to be reduced in mutation-positive patients with HCM in some studies even in the absence of left ventricular hypertrophy (LVH). Strain is a sensitive tool in detecting early systolic abnormalities in patients with hypertrophic cardiomyopathy (HCM). Our goal is to examine novel echocardiographic characteristics of phenotype-negative carriers for a known sarcomeric gene mutation for HCM.
Methods
We evaluated 41 consecutive subjects with a known myosin binding protein C3 (MYBPC3) mutation (c.3330+2T>G). Subjects who were mutation-positive without LVH (G+/LVH−, n=35) were compared to healthy controls (n=30) regarding tissue Doppler and segmental longitudinal strain measures.
Results
The G+/LVH− group was similar to the normal controls with respect to chamber size, LV mass index, and most diastolic filling parameters, including tissue Doppler derived Ea. Global longitudinal strain was similar for both groups (20.3 ± 2.1 vs. 19.8 ± 1.8; p=0.36) although regional segment analysis showed a notable reduction in the basal septum (16.8 ± 3.1 vs. 19.0 ± 4.0%, p=0.02) and increase in the basal posterior (22.5 ± 5.2 vs. 17.9 ± 5.2, p=0.001) as well as mid posterior (21.8 ± 4.7 vs. 18.2 ± 3.0, p=0.001) walls.
Conclusions
In our cohort of phenotype-negative carriers of a specific MYBPC3 mutation, there were minimal differences in conventional 2-dimensional, Doppler, and speckle-tracking derived parameters of systolic and diastolic function compared to that of normal subjects. The presence of regional alterations in strain indicative of the presence of underlying subclinical disease requires further validation.
doi:10.1016/j.ahj.2011.05.018
PMCID: PMC3155874  PMID: 21835286
hypertrophic cardiomyopathy; genetic heart disease; echocardiography; longitudinal strain
21.  How Similar Are the Mice to Men? Between-Species Comparison of Left Ventricular Mechanics Using Strain Imaging 
PLoS ONE  2012;7(6):e40061.
Background
While mammalian heart size maintains constant proportion to whole body size, scaling of left ventricular (LV) function parameters shows a more complex scaling pattern. We used 2-D speckle tracking strain imaging to determine whether LV myocardial strains and strain rates scale to heart size.
Methods
We studied 18 mice, 15 rats, 6 rabbits, 12 dogs and 20 human volunteers by 2-D echocardiography. Relationship between longitudinal or circumferential strains/strain rates (SLong/SRLong, SCirc/SRCirc), and LV end-diastolic volume (EDV) or mass were assessed by the allometric (power-law) equation Y = kMβ.
Results
Mean LV mass in individual species varied from 0.038 to 134 g, LV EDV varied from 0.015 to 102 ml, while RR interval varied from 81 to 1090 ms. While SLong increased with increasing LV EDV or mass (β values 0.047±0.006 and 0.051±0.005, p<0.0001 vs. 0 for both) SCirc was unchanged (p = NS for both LV EDV or mass). Systolic and diastolic SRLong and SRCirc showed inverse correlations to LV EDV or mass (p<0.0001 vs. 0 for all comparisons). The ratio between SLong and SCirc increased with increasing values of LV EDV or mass (β values 0.039±0.010 and 0.040±0.011, p>0.0003 for both).
Conclusions
While SCirc is unchanged, SLong increases with increasing heart size, indicating that large mammals rely more on long axis contribution to systolic function. SRLong and SRCirc, both diastolic and systolic, show an expected decrease with increasing heart size.
doi:10.1371/journal.pone.0040061
PMCID: PMC3386935  PMID: 22768220
22.  Renal Dysfunction is a Stronger Determinant of Systemic Neutrophil Gelatinase-Associated Lipocalin Levels Than Myocardial Dysfunction in Systolic Heart Failure 
Journal of cardiac failure  2011;17(6):472-478.
Background
Neutrophil gelatinase-associated lipocalin (NGAL) is released by renal tubular cells in response to inflammation and injury. Recent studies have demonstrated that NGAL is upregulated in cardiomyocytes within the failing myocardium. However, the overall relationship between systemic NGAL levels and myocardial structure and performance has not been established.
Methods and Results
We measured systemic NGAL levels in 130 subjects with chronic systolic heart failure (HF) and comprehensive echocardiographic evaluation, as well as 69 subjects with acute decompensated systolic HF and hemodynamic evaluation. In the chronic HF cohort, higher plasma NGAL levels were modestly associated with increasing age (r= 0.18, p=0.035), higher NYHA class (rank sums, p=0.022) and impaired renal function (eGFR: r= −0.53, p<0.0001; cystatin C: r= 0.60, p<0.0001). Plasma NGAL levels were modestly associated with indices of diastolic dysfunction (mitral E/Ea: r= 0.27, p=0.002; LAVi, r= 0.25, p=0.011; tricuspid E/Ea: r= 0.20, p=0.029), but not after adjustment for renal function (p>0.10 for all). In Cox proportional hazards analysis, plasma NGAL predicted cardiac death or transplantation after adjustment for age, gender, LVEF, and mitral E/Ea (Hazard ratio 1.68, 95% confidence interval 1.08 – 2.57, p=0.022), but not after adjustment for renal function (p=0.83). In the acute HF cohort, we did not observe any relationship between NGAL and hemodynamic indices, but NGAL strongly correlated with renal function.
Conclusions
Systemic NGAL levels are largely determined by underlying impairment of renal rather than myocardial function. Our findings did not support any relationship or prognostic significance between systemic NGAL levels and indices of cardiac structure and function after adjustment for underlying renal function.
doi:10.1016/j.cardfail.2011.02.003
PMCID: PMC3105247  PMID: 21624735
Congestive heart failure; NGAL; renal insufficiency; cardio-renal
23.  DOPPLER ECHOCARDIOGRAPHIC ASSESSMENT OF VALVAR REGURGITATION 
Heart  2002;88(6):651-657.
PMCID: PMC1767478  PMID: 12433911
Doppler echocardiography; valvar regurgitation; proximal convergence method; mitral valve; aortic valve
24.  Tissue Doppler Imaging in the Estimation of Intracardiac Filling Pressure in Decompensated Patients with Advanced Systolic Heart Failure 
Circulation  2008;119(1):62-70.
Background
Early transmitral velocity / tissue Doppler mitral annular early diastolic velocity (E/Ea) has been correlated with pulmonary capillary wedge pressure (PCWP) in a wide variety of cardiac conditions. The objective of this study was to determine the reliability of mitral E/Ea for predicting PCWP in patients admitted for advanced decompensated heart failure (ADHF).
Methods and Results
Prospective consecutive patients with ADHF (ejection fraction [EF] ≤30%, NYHA class III-IV symptoms) underwent simultaneous echocardiographic and hemodynamic evaluation on admission and after 48 hours of intensive medical therapy. A total of 106 patients were included (mean age 57 ±12 years, EF 24 ±8%, PCWP 21 ±7 mmHg, mitral E/Ea 20 ±12). There was a lack of correlation between mitral E/Ea and PCWP, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy. Overall, mitral E/Ea was similar among patients with PCWP > and ≤ 18 mmHg, and sensitivity and specificity for mitral E/Ea > 15 to identify a PCWP > 18 mmHg was 66% and 50%, respectively. Contrary to prior reports, we did not observe any direct association between changes in PCWP and changes in mitral E/Ea.
Conclusion
In decompensated patients with advanced systolic heart failure, tissue Doppler derived mitral E/Ea may not be as reliable in predicting intracardiac filling pressures, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy.
doi:10.1161/CIRCULATIONAHA.108.779223
PMCID: PMC3169300  PMID: 19075104
heart failure; hemodynamics; diastole; remodeling; echocardiography
25.  Right Ventricular Response to Intensive Medical Therapy in Advanced Decompensated Heart Failure 
Circulation. Heart failure  2010;3(3):340-346.
Background
Right ventricular (RV) systolic dysfunction is a strong predictor of adverse outcomes in heart failure, yet quantitatively assessing the impact of therapy on this condition is difficult. Our objective was to compare the clinical significance of changes in RV echocardiographic indices in response to intensive medical treatment in patients admitted to the hospital with acute decompensated heart failure (ADHF).
Methods and Results
Serial comprehensive echocardiography was performed in 62 consecutive patients with ADHF, and adverse events (death, cardiac transplantation, assist device, heart failure rehospitalization) were prospectively documented. RV peak systolic strain was assessed using speckle-tracking longitudinal strain analysis as the average of the basal, mid-, and apical segment of the RV free wall. Other conventional parameters of RV function (RV fractional area change, RV myocardial performance index, tricuspid annular peak systolic excursion, and tissue Doppler peak tricuspid annular systolic velocity) were measured for comparison. In our study cohort [left ventricular ejection fraction, 26±10%; cardiac index, 2.0±0.6 L/(min · m2)], overall mean RV peak systolic strain was –14±4% at baseline and –15±4% at 48 to 72 hours (P=0.27). Among all the RV functional indices measured, only RV peak systolic strain at 48 to 72 hours was associated with adverse events (P=0.02). In particular, improvement in RV peak systolic strain after intensive medical treatment was associated with lower adverse events in this patient population (26% versus 78%; hazard ratio, 0.13; 95% CI, 0.02 to 0.84; P=0.02).
Conclusion
Dynamic improvement in RV mechanics in response to intensive medical therapy was associated with lower long-term adverse events in patients with ADHF than in patients not showing improvement.
doi:10.1161/CIRCHEARTFAILURE.109.900134
PMCID: PMC3060051  PMID: 20176715
echocardiography; heart failure; hemodynamics; prognosis; right ventricle

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