Chun G. Schiros

A Randomized Controlled Phase IIb Trial of Beta1-Receptor Blockade for Chronic Degenerative Mitral Regurgitation

OBJECTIVES The purpose of the study was to evaluate the effect of long-term β(1)-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR). BACKGROUND Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function. METHODS Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or β(1)-AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end-systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate. RESULTS Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the β(1)-AR blockade group required mitral valve surgery (p = 0.23). CONCLUSIONS β(1)-AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload-Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428).

Magnetic Resonance Imaging With 3-Dimensional Analysis of Left Ventricular Remodeling in Isolated Mitral Regurgitation Implications Beyond Dimensions

Background— Although surgery is indicated in patients with mitral regurgitation (MR) when left ventricular (LV) end-systolic (LVES) dimension is >40 mm, LV ejection fraction may decrease after mitral valve surgery. We hypothesize that significant LV remodeling before surgery is not reflected by standard echocardiographic parameters measured at the base of the heart. Methods and Results— Ninety-four patients (age, 54±11 years; 38% female) with degenerative isolated MR underwent cine magnetic resonance imaging with tissue tagging and 3-dimensional analysis. In 51 control subjects (age, 44±14 years; 53% female), the relation between LVES volume (LVESV) and LVES dimension was quadratic, whereas in 94 MR patients, this relation was cubic, indicating a greater increase in LVESV per LVES dimension among MR patients. Moreover, magnetic resonance imaging LVESV from summated serial short-axis slices was significantly greater than LVESV assessed with the Bullet formula in MR patients, attributed to a more spherical remodeling distal to the tips of the papillary muscles (P<0.001). Thirty-five patients underwent mitral valve repair per current guideline recommendations. LV ejection fraction decreased from 61±7% to 54±8% (P<0.0001) and maximum shortening decreased significantly below normal at 1 year postoperatively (P<0.0001). Despite normalization of LV stroke volume and LV end-diastolic volume/mass ratio, there was a persistent significant increase in distal LVES 3-dimensional radius/wall thickness ratio and LVESV index after surgery. Conclusions— Despite apparently preserved LVES dimension, MR patients demonstrate significant spherical mid to apical LVES remodeling that contributes to higher LVESV than predicted by standard geometry-based calculations. Decreased LV strain after surgery suggests that a volumetric analysis of LV remodeling and function may be preferred to evaluate disease progression in isolated MR.

Diagnostic Accuracy of Tissue Doppler Index E/è for Evaluating Left Ventricular Filling Pressure and Diastolic Dysfunction/Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta‐Analysis

Background Tissue Doppler index E/è is used clinically and in multidisciplinary research for estimation of left ventricular filling pressure (LVFP) and diastolic dysfunction (DD)/heart failure with preserved ejection fraction (HFpEF). Its diagnostic accuracy is not well studied. Methods and Results From the PubMed, Scopus, Embase, and Cochrane databases, we identified 24 studies reporting E/è and invasive LVFP in preserved EF (≥50%). In random‐effects models, E/è had poor to mediocre linear correlation with LVFP. Summary sensitivity and specificity (with 95% CIs) for the American Society of Echocardiography–recommended E/è cutoffs (lateral, mean, and septal, respectively) to identify elevated LVFP was estimated by using hierarchical summary receiver operating characteristic analysis. Summary sensitivity was 30% (9–48%), 37% (13–61%), and 24% (6–46%), and summary specificity was 92% (82–100%), 91% (80–99%), and 98% (92–100%). Positive likelihood ratio (LR+) was <5 for lateral and mean E/è. LR+ was slightly >10 for septal E/è obtained from 4 studies (cumulative sample size <220). For excluding elevated LVFP, summary sensitivity for E/è (lateral, mean, and septal, respectively) was 64% (38–86%), 36% (3–74%), and 50% (14–81%), while summary specificity was 73% (54–89%), 83% (49–100%), and 89% (66–100%). Because of data set limitations, meaningful inference for identifying HFpEF by using E/è could not be drawn. With the use of quality assessment tool for diagnostic accuracy studies (Quality Assessment of Diagnostic Accuracy Studies questionnaire), we found substantial risks of bias and/or applicability. Conclusions There is insufficient evidence to support that E/è can reliably estimate LVFP in preserved EF. The diagnostic accuracy of E/è to identify/exclude elevated LVFP and DD/HFpEF is limited and requires further validation in a well‐designed prospective clinical trial.

Increased Sarcolipin Expression and Adrenergic Drive in Humans With Preserved Left Ventricular Ejection Fraction and Chronic Isolated Mitral Regurgitation

Background— There is currently no therapy proven to attenuate left ventricular (LV) dilatation and dysfunction in volume overload induced by isolated mitral regurgitation (MR). To better understand molecular signatures underlying isolated MR, we performed LV gene expression analyses and overlaid regulated genes into ingenuity pathway analysis in patients with isolated MR. Methods and Results— Gene arrays from LV tissue of 35 patients, taken at the time of surgical repair for isolated MR, were compared with 13 normal controls. Cine-MRI was performed in 31 patients before surgery to measure LV function and volume from serial short-axis summation. LV end-diastolic volume was 2-fold (P=0.005) higher in MR patients than in normal controls, and LV ejection fraction was 64±7% (50%–79%) in MR patients. Ingenuity pathway analysis identified significant activation of pathways involved in &bgr;-adrenergic, cAMP, and G-protein–coupled signaling, whereas there was downregulation of pathways associated with complement activation and acute phase response. SERCA2a and phospholamban protein were unchanged in MR versus control left ventricles. However, mRNA and protein levels of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) regulatory protein sarcolipin, which is predominantly expressed in normal atria, were increased 12- and 6-fold, respectively. Immunofluorescence analysis confirmed the absence of sarcolipin in normal left ventricles and its marked upregulation in MR left ventricles. Conclusions— These results demonstrate alterations in multiple pathways associated with &bgr;-adrenergic signaling and sarcolipin in the left ventricles of patients with isolated MR and LV ejection fraction >50%, suggesting a beneficial role for &bgr;-adrenergic blockade in isolated MR.

Three-dimensional plus time biventricular strain from tagged MR images by phase-unwrapped harmonic phase.

To validate a method called bi‐ventricular strain unwrapped phase (BiSUP) for reconstructing three‐dimensional plus time (3D+t) biventricular strain maps from phase‐unwrapped harmonic phase (HARP) images derived from tagged cardiac magnetic resonance imaging (MRI).

Mitral Annular Kinetics, Left Atrial, and Left Ventricular Diastolic Function Post Mitral Valve Repair in Degenerative Mitral Regurgitation

Objective The relationship of mitral annular (MA) kinetics to left ventricular (LV) and left atrial (LA) function before and after mitral valve (MV) repair has not been well studied. Here we sought to provide comprehensive analysis that relates to MA motions, and LA and LV diastolic function post MV repair. Methods Three-dimensional analyses of mitral annular motion, LA function, and LV volumetric and diastolic strain rates were performed on 35 degenerative mitral regurgitation (MR) patients at baseline and 1-year post MV repair, and 51 normal controls, utilizing cardiac magnetic resonance imaging with tissue tagging. Results All had normal LV ejection fraction (EF) at baseline. LV and LA EFs decreased 1-year post-surgery vs. controls. LV early diastolic myocardial strain rates decreased post-surgery along with decreases in normalized early diastolic filling rate, E/A ratio, and early diastolic MA relaxation rates. Post-surgical LA late active kick remained higher in MR patients vs. control. LV and LA EFs were significantly associated with peak MA centroid to apex shortening. Furthermore, during LV systolic phase, peak LV ejection and LA filling rates were significantly correlated with peak MA centroid to apex shortening rate, respectively. While during LV diastolic phase, both peak early diastolic MA centroid to apex relaxation rate and LA ejection rate were positively significantly associated with LV peak early diastolic filling rate. Conclusion MA motion is significantly associated with LA and LV function. Mitral annular motion, left atrial function, and LV diastolic strain rates are still impaired 1 year post MV repair. Long-term effects of these impairments should be prospectively evaluated.

Improved Right Ventricular Performance with Increased Tricuspid Annular Excursion in Athlete’s Heart

Background Marathon runners (MTH) and patients with mitral regurgitation (MR) exhibit left ventricular (LV) overload, and LV geometric changes in these groups have been reported. In this study, right ventricular (RV) adaptation to chronic volume overload was evaluated in MTH and MR and normal controls together with interventricular septal remodeling and tricuspid annulus (TA) motion. Methods A total of 60 age-matched subjects (including 19 MTH, 17 isolated chronic compensated MR patients, and 24 normal subjects) underwent conventional cine and tagged cardiac magnetic resonance imaging. Myocardial strain and curvature were computed on the interventricular septum and RV free wall. A dual-propagation technique was applied to construct RV volume-time curves for a single cardiac cycle. Similarly, the TA was tracked throughout the cardiac cycle to create displacement over time curve. Results Septal curvature was significantly lower in MTH and MR compared to controls. No significant differences in RV free-wall strain or RV ejection fraction were noted among the three groups. However, longitudinal TA excursion was significantly higher in MTH compared to controls (p = 0.0061). The peak late diastolic TA velocity in MR was significantly faster than MTH (p = 0.0031) and controls (p = 0.020). Conclusion Increased TA kinetics allows for improved RV performance in MTH. Septal remodeling was observed in both MR and MTH, therefore a direct relationship of septal remodeling to TA kinetics in athlete’s heart could not be elucidated in this study.

Modified treatment approach using cardiovascular disease risk calculator for primary prevention.

Background The recent guidelines for preventing atherosclerotic cardiovascular events are an important advancement. For primary prevention, statins are recommended if the ten-year risk is ≥ 5% (consideration for therapy) or ≥ 7.5% (definitive treatment unless contraindication after discussion). We rationalized that a significant cohort with ten-year risk below the treatment thresholds would predictably surpass them within the recommended 4–6 year window for reassessing the ten-year risk. As atherosclerosis is a progressive disease, these individuals may therefore benefit with more aggressive therapies even at baseline. Methods and Findings We used publicly available NHANES dataset for ten-year risk calculation. There were 1805 participants. To evaluate the ten-year risk change at five years, we considered two scenarios: no change in the baseline parameters except increased age by five (No Change) and alternatively 10% improvement in systolic BP, total and HDL-c, no smoking with five-year increase in age (Reduced Risk Profile). Amongst non-diabetics with <5% risk at baseline, 35% reached or exceeded 5% risk in five years (5% reached or exceed the 7.5% risk) with No Change and 9% reached or exceeded 5% risk in five years (none reached 7.5% risk) with Reduced Risk Profile; furthermore, 94% of the non-diabetic cohort with baseline risk between 3.5%–5% would exceed the 5% and/or 7.5% boundary limit with No Change. Amongst non-diabetics with 5–7.5% baseline risks, 87% reached or exceeded 7.5% with No Change while 30% reached or exceeded 7.5% risk with Reduced Risk Profile. Conclusions A significant population cohort at levels below the treatment thresholds will predictably exceed these limits with time with or without improvement in modifiable risk factors and may benefit with more aggressive therapy at baseline. We provide an improved risk calculator that allows for integrating expected risk modification into discussion with an individual. This needs to be prospectively tested in clinical trials.

Left Ventricular Torsion Shear Angle Volume Approach for Noninvasive Evaluation of Diastolic Dysfunction in Preserved Ejection Fraction

Background Accurate noninvasive diagnostic tools for evaluating left ventricular (LV) diastolic dysfunction (LVDD) are limited in preserved LV ejection fraction. We previously proposed the relationship of normalized rate of change in LV torsion shear angle (φ′) to corresponding rate of change in LV volume (V′) during early diastole (represented as −dφ′/dV′) as a measure of LV diastolic function. We prospectively evaluated diagnostic accuracy of −dφ′/dV′ in respect to invasive LV parameters. Methods and Results Participants (n=36, age 61±7 years) with LV ejection fraction ≥50% and no acute myocardial infarction undergoing coronary angiography for chest pain and/or dyspnea evaluation were studied. High‐fidelity invasive LV pressure measurements and cardiac magnetic resonance imaging with tissue tagging were performed. τ, the time constant of LV diastolic relaxation, was 58±10 milliseconds (mean±SD), and LV end‐diastolic pressure was 14.5±5.5 mm Hg. Cardiac magnetic resonance imaging‐derived −dφ′/dV′ was 5.6±3.7. The value of −dφ′/dV′ correlated with both τ and LV end‐diastolic pressure (r=0.39 and 0.36, respectively, P<0.05). LVDD was defined as τ>48 milliseconds and LV end‐diastolic pressure >12 mm Hg (LVDD1), or, alternatively, τ>48 milliseconds and LV end‐diastolic pressure >16 mm Hg (LVDD2). Area under the curve (AUC) of −dφ′/dV′ for identifying LVDD1 was 0.83 (0.67‐0.98, P=0.001), with sensitivity/specificity of 72%/100% for −dφ′/dV′ ≥6.2. AUC of −dφ′/dV′ for identifying LVDD_2 was 0.82 (0.64‐1.00, P=0.006), with sensitivity/specificity of 76%/85% for −dφ′/dV′ ≥6.9. There were good limits of agreement between pre‐ and post‐nitroglycerin −dφ′/dV′. Conclusions The −dφ′/dV′ obtained from the LV torsion volume loop is a promising parameter for assessing global LVDD with preserved LV ejection fraction and requires further evaluation.

Left ventricular diastolic dysfunction index based on non-invasive measurements

Background Echocardiographic tissue Doppler or magnetic resonance imaging (MRI) measurements of early diastolic mitral annular velocity with other appropriate parameters are frequently used as a non-invasive diagnostic tool of diastolic dysfunction. Previously published global approach utilizing normalized left ventricular (LV) torsion shear angle volume loop ( _hat V_hat loop) was proposed to provide a new global description of LV diastolic function. The purpose of this study was to evaluate the discriminant power of these non-invasive parameters in identifying elevated LV end-diastolic pressure (LVEDP) (i.e. LVEDP≥15ml) and provide a non-invasive index to predict elevated LVEDP. Methods A group of 23 patients with LV ejection fraction≥50% without acute infarct undergoing cardiac catheterization that did not undergo percutaneous coronary intervention were studied using high-fidelity pressure measurement. Echocardiogram with flow and tissue Doppler quantification was performed on the same date of cardiac catheterization for all participants. Cine and tagged cardiac MRI were performed on all subjects, followed by comprehensive volumetric and strain analysis. The database consisted of five parameters collected from all subjects: torsion hysteresis area (THA), peak -d_hat/dV_hat at early diastole, MRI derived E/AMRI, echocardiographic derived E/A and E/e’. Stepwise variable selection was applied to select parameters with significance level of leave out and stay in equal to 0.15. A logistic regression classifier was used to construct the non-invasive index for identifying elevated LVEDP based on the selected parameters. The classifier’s prediction performance was analyzed using a Receiver-Operating Characteristic (ROC) curve and expressed as its sensitivity, specificity, accuracy and area under the curve (AUC). Results