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1.  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
2.  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
8.  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
9.  Non-invasive assessment of left ventricular relaxation during atrial fibrillation using mitral flow propagation velocity† 
Aims
To elucidate the usefulness of the early diastolic mitral flow propagation velocity (Vp) obtained from colour M-mode Doppler for non-invasively assessing left-ventricular (LV) relaxation during atrial fibrillation (AF).
Methods and results
Ten healthy adult dogs were studied to correlate Vp with the invasive minimum value of the first derivative of LV pressure decay (dP/dtmin) and the time constant of isovolumic LV pressure decay (τ) at baseline, during rapid and slow AF, and during AF after inducing myocardial infarction. There were significant positive and negative curvilinear relationships between Vp and dP/dtmin and τ, respectively, during rapid AF. After slowing the ventricular rate, the average value of Vp increased, while dP/dtmin increased and τ decreased. After inducing myocardial infarction, the average value of Vp decreased, while dP/dtmin decreased and τ increased.
Conclusion
The non-invasively obtained Vp evaluates LV relaxation even during AF regardless of ventricular rhythm or the presence of pathological changes.
doi:10.1093/ejechocard/jep083
PMCID: PMC2760444  PMID: 19692424
Mitral flow propagation velocity; Atrial fibrillation; The first derivative of left ventricular pressure decay; The time constant of isovolumic left ventricular pressure decay
10.  Blockade of NF-κB using IκBκ dominant negative mice ameliorates cardiac hypertrophy in myotrophin overexpressed transgenic mice 
Journal of molecular biology  2008;381(3):559-568.
NF-κB is a ubiquitous transcription factor that regulates various kinds of genes including inflammatory molecules, macrophage infiltration factors, cell adhesion molecules, etc., in various disease processes including cardiac hypertrophy and heart failure (HF). Previously, we have demonstrated that activation of NF-κB was required in myotrophin induced cardiac hypertrophy, in spontaneously hypertensive rats (SHR) and in dilated cardiomyopathy (DCM) human hearts. Moreover, our recent study using the myotrophin overexpressed transgenic mouse (Myo-Tg) model showed that shRNA-mediated knock down of NF-κB significantly attenuated cardiac mass associated with improved cardiac function. Although, it has been shown that NF-κB is substantially involved in cardiovascular remodeling, it is not clear whether the continuous blockade of NF-κB is effective in cardiovascular remodeling. To address this question, we took a genetic approach using IκBα triple mutant mice (3M) bred with Myo-Tg mice (a progressive hypertrophy/HF model). The double transgenic mice (Myo-3M) displayed an attenuated cardiac hypertrophy (9.8 ± 0.62 vs 5.4 ± 0.34, p<0.001) and improved cardiac function associated with significant inhibition of the NF-κB signaling cascade, hypertrophy marker gene expression, inflammatory and macrophage gene expression at 24 weeks of age compared to Myo-Tg mice. NF-κB-targeted gene array profiling displayed several important genes were significantly down regulated in Myo-3M mice compared to Myo-Tg mice. Furthermore, Myo-3M did not show any changes of apoptotic gene expression indicating that complete inhibition of NF-κB activation reduces further pro-inflammatory reactions without affecting susceptibility to apoptosis. Therefore, development of therapeutic strategies targeting NF-κB may provide an effective approach to prevent adverse cardiac pathophysiological consequences.
doi:10.1016/j.jmb.2008.05.076
PMCID: PMC2688722  PMID: 18620706
NF-κB; IκBκ dominant negative mice; cardiac hypertrophy; myotrophin; macrophage; NF-κB-gene array
11.  Prevention of Cardiac Hypertrophy and Heart Failure by Silencing of NF-κB 
Journal of molecular biology  2007;375(3):637-649.
Activation of the nuclear factor κB (NF-κB) signaling pathway may be associated with the development of cardiac hypertrophy and transition to heart failure (HF). The transgenic mouse, Myo-Tg, develops hypertrophy and HF as a result of overexpression of myotrophin in the heart associated with elevated level of NF-κB activity. Using this mouse model and an NF-κB-targeted gene array, we first determined the components of NF-κB signaling cascade and the NF-κB-linked genes that are expressed during the progression to cardiac hypertrophy and HF. Secondly, we explored the effects of inhibition of NF-κB signaling events by using gene knock-down approach: RNA interference (RNAi) through delivery of a short hairpin RNA (shRNA) against NF-κB-p65 using a lentiviral vector (L-sh-p65). When the shRNA was delivered directly into hearts of 10-week old Myo-Tg mice, a significant regression of cardiac hypertrophy, associated with significant reduction in NF-κB activation and atrial natriuretic factor (ANF) expression. Our data suggest, for the first time, that inhibition of NF-κB using direct gene delivery of sh-p65-RNA results in regression of cardiac hypertrophy. This data validates NF-κB as a therapeutic target to prevent hypertrophy/HF.
doi:10.1016/j.jmb.2007.10.006
PMCID: PMC2277468  PMID: 18037434
myotrophin; NF-κB; RNA interference; transgenic mice; hypertrophy; heart failure
12.  Myocardial scar burden predicts survival benefit with implantable cardioverter defibrillator implantation in patients with severe ischaemic cardiomyopathy: influence of gender 
Heart  2013;100(3):206-213.
Objective
We sought to assess the impact of myocardial scar burden (MSB) on the association between implantable cardioverter defibrillator (ICD) implantation and mortality in patients with ischaemic cardiomyopathy (ICM) and left ventricular EF ≤40%. In addition, we sought to determine the impact of gender on survival benefit with ICD implantation.
Design
Retrospective observational study.
Setting
Single US tertiary care centre.
Patients
Consecutive patients with significant ICM who underwent delayed hyperenhancement-MRI between 2002 and 2006.
Interventions
ICD implantation.
Main outcome measures
All-cause mortality and cardiac transplantation.
Results
Follow-up of 450 consecutive patients, over a mean of 5.8 years, identified 186 deaths. Cox proportional hazard modelling was used to evaluate associations among MSB, gender and ICD with respect to all-cause death as the primary endpoint. ICDs were implanted in 163 (36%) patients. On multivariable analysis, Scar% (χ2 28.21, p<0.001), Gender (χ2 12.39, p=0.015) and ICD (χ2 9.57, p=0.022) were independent predictors of mortality after adjusting for multiple parameters. An interaction between MSB×ICD (χ2 9.47, p=0.009) demonstrated significant differential survival with ICD based on MSB severity. Additionally, Scar%×ICD×Gender (χ2 6.18, p=0.048) suggested that men with larger MSB had significant survival benefit with ICD, but men with smaller MSB derived limited benefit with ICD implantation. However, the inverse relationship was found in women.
Conclusions
MSB is a powerful independent predictor of mortality in patients with and without ICD implantation. In addition, MSB may predict gender-based significant differences in survival benefit from ICDs in patients with severe ICM.
doi:10.1136/heartjnl-2013-304261
PMCID: PMC3913110  PMID: 24186562
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