Predictors of long-term outcomes in patients with significant myxomatous mitral regurgitation undergoing exercise echocardiography.

BACKGROUND: Significant myxomatous mitral regurgitation leads to progressive left ventricular (LV) decline, resulting in congestive heart failure and death. Such patients benefit from mitral valve surgery. Exercise echocardiography aids in risk stratification and helps decide surgical timing. We sought to assess predictors of outcomes in such patients undergoing exercise echocardiography. METHODS AND RESULTS: This is an observational study of 884 consecutive patients (age, 58 ± 14 years; 67% men) with grade III+ or greater myxomatous mitral regurgitation who underwent exercise echocardiography between January 2000 and December 2011 (excluding functional mitral regurgitation, prior valvular surgery, hypertrophic cardiomyopathy, rheumatic valvular disease, or greater than mild mitral stenosis). Clinical and echocardiographic data (mitral regurgitation, LV ejection fraction, LV dimensions, right ventricular systolic pressure) and exercise variables (metabolic equivalents, heart rate recovery at 1 minute after exercise) were recorded. Composite events of death, myocardial infarction, stroke, and progression to congestive heart failure were recorded. Mean LV ejection fraction, indexed LV end-systolic dimension, resting right ventricular systolic pressure, peak stress right ventricular systolic pressure, metabolic equivalents achieved, and heart rate recovery were 58 ± 5%, 1.6 ± 0.4 mm/m(2), 31 ± 12 mm Hg, 46 ± 17 mm Hg, 9.6 ± 3, and 33 ± 14 beats, respectively. During 6.4 ± 4 years of follow-up, there were 87 events. On stepwise multivariable Cox analysis, percent of age/sex-predicted metabolic equivalents (hazard ratio, 0.99; 95% confidence interval, 0.98-0.99; P=0.005), heart rate recovery (hazard ratio, 0.29; 95% confidence interval, 0.17-0.50; P<0.001), resting right ventricular systolic pressure (hazard ratio, 1.03; 95% confidence interval, 1.004-1.05; P=0.02), atrial fibrillation (hazard ratio, 1.91; 95% confidence interval, 1.07-3.41; P=0.03), and LV ejection fraction (hazard ratio, 0.96; 95% confidence interval, 0.92-0.99; P=0.04) predicted outcomes. CONCLUSIONS: In patients with grade III+ or greater myxomatous mitral regurgitation undergoing exercise echocardiography, lower percent of age/sex-predicted metabolic equivalents, lower heart rate recovery, atrial fibrillation, lower LV ejection fraction, and high resting right ventricular systolic pressure predicted worse outcomes.

Efficacy of coxsackievirus A21 against drug-resistant neoplastic B cells.

Primary drug resistance and minimal residual disease are major challenges in the treatment of B cell neoplasms. Therefore, this study aimed to identify a novel treatment capable of eradicating malignant B cells and drug-resistant disease. Oncolytic viruses eradicate malignant cells by direct oncolysis and activation of anti-tumor immunity, have proven anti-cancer efficacy, and are safe and well tolerated in clinical use. Here, we demonstrate that the oncolytic virus coxsackievirus A21 can kill a range of B cell neoplasms, irrespective of an anti-viral interferon response. Moreover, CVA21 retained its capacity to kill drug-resistant B cell neoplasms, where drug resistance was induced by co-culture with tumor microenvironment support. In some cases, CVA21 efficacy was actually enhanced, in accordance with increased expression of the viral entry receptor ICAM-1. Importantly, the data confirmed preferential killing of malignant B cells and CVA21 dependence on oncogenic B cell signaling pathways. Significantly, CVA21 also activated natural killer (NK) cells to kill neoplastic B cells and drug-resistant B cells remained susceptible to NK cell-mediated lysis. Overall, these data reveal a dual mode of action of CVA21 against drug-resistant B cells and support the development of CVA21 for the treatment of B cell neoplasms.

Past, Present and Future of Oncolytic Reovirus.

Oncolytic virotherapy (OVT) has received significant attention in recent years, especially since the approval of talimogene Laherparepvec (T-VEC) in 2015 by the Food and Drug administration (FDA). Mechanistic studies of oncolytic viruses (OVs) have revealed that most, if not all, OVs induce direct oncolysis and stimulate innate and adaptive anti-tumour immunity. With the advancement of tumour modelling, allowing characterisation of the effects of tumour microenvironment (TME) components and identification of the cellular mechanisms required for cell death (both direct oncolysis and anti-tumour immune responses), it is clear that a "one size fits all" approach is not applicable to all OVs, or indeed the same OV across different tumour types and disease locations. This article will provide an unbiased review of oncolytic reovirus (clinically formulated as pelareorep), including the molecular and cellular requirements for reovirus oncolysis and anti-tumour immunity, reports of pre-clinical efficacy and its overall clinical trajectory. Moreover, as it is now abundantly clear that the true potential of all OVs, including reovirus, will only be reached upon the development of synergistic combination strategies, reovirus combination therapeutics will be discussed, including the limitations and challenges that remain to harness the full potential of this promising therapeutic agent.

Synergistic Utility of Brain Natriuretic Peptide and Left Ventricular Strain in Patients With Significant Aortic Stenosis.

BACKGROUND: In aortic stenosis (AS), symptoms and left ventricular (LV) dysfunction represent a later disease state, and objective parameters that identify incipient LV dysfunction are needed. We sought to determine prognostic utility of brain natriuretic peptide (BNP) and left ventricular global longitudinal strain (LV-GLS) in patients with aortic valve area <1.3 cm(2). METHODS AND RESULTS: Five-hundred and thirty-one patients between January 2007 and December 2008 with aortic valve area <1.3 cm(2) (86% with aortic valve area ≤1.1 cm(2)) and left ventricular ejection fraction ≥50% who had BNP drawn ≤90 days from initial echo were included. Society of Thoracic Surgeons (STS) score and mortality were recorded. Mean STS score, glomerular filtration rate, and median BNP were 11±5, 73±35 mL/min per 1.73 m , and 141 (60-313) pg/mL, respectively; 78% were in New York Heart Association class ≥II. Mean LV-stroke volume index (LV-SVI) and LV-GLS were 39±10 mL/m(2) and -13.9±3%. At 4.7±2 years, 405 patients (76%) underwent aortic valve replacement; 161 died (30%). On multivariable survival analysis, age (hazard ratio [HR] 1.46), New York Heart Association class (HR 1.27), coronary artery disease (HR 1.72), decreasing glomerular filtration rate (HR 1.15), increasing BNP (HR 1.16), worsening LV-GLS (HR 1.13) and aortic valve replacement (time dependent) (HR 0.34) predicted survival (all P<0.01). For mortality, the c-statistic incrementally increased as follows (all P<0.01): STS score (0.60 [0.58-0.64]), STS score+BNP (0.67 [0.62-0.70]), and STS score+BNP+LV-GLS (0.74 [0.68-0.78]). CONCLUSIONS: In normal LVEF patients with significant aortic stenosis, BNP and LV-GLS provide incremental (additive not duplicative) prognostic information over established predictors, suggesting that both play a synergistic role in defining outcomes.

Predictors of Long-Term Outcomes in Asymptomatic Patients With Severe Aortic Stenosis and Preserved Left Ventricular Systolic Function Undergoing Exercise Echocardiography.

BACKGROUND: In asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction, we sought to assess incremental prognostic utility of exercise stress echocardiography. METHODS AND RESULTS: We studied 533 such patients (age, 66±13 years; 78% men; 31% with coronary artery disease) who underwent exercise stress echocardiography between 2001 and 2012. Clinical, echocardiographic, and exercise variables (metabolic equivalents [METs], % of age-sex-predicted METs and heart rate recovery at first minute post exercise) were recorded. The end point was all-cause mortality. The Society of Thoracic Surgeons score, left ventricular ejection fraction, mean resting aortic valve (AV) gradient, indexed AV area, METs, and heart rate recovery were 2.9±3%, 58±4%, 35±11 mm Hg, 0.47±0.1 cm(2)/m(2), 7.8±3, and 26±12 bpm, respectively. Only 50% achieved >100%, whereas 26% achieved <85% age-sex-predicted METs. There were no major exercise stress echocardiography-related complications. Over 6.9±3 years, 341 (64%) underwent AV replacement (54% isolated), and there were 104 (20%) deaths. On multivariable Cox proportional hazard survival analysis, a higher Society of Thoracic Surgeons score (hazard ratio, 1.21), lower % age-sex-predicted METs (hazard ratio 1.15), and slower heart rate recovery (hazard ratio, 1.22) were associated with higher longer-term mortality, whereas AV replacement (time-dependent covariate, hazard ratio, 0.26) was associated with improved survival. The addition of % age-sex-predicted METs to the Society of Thoracic Surgeons score resulted in significant reclassification of longer-term mortality risk (integrated discrimination index, 0.07 [0.03-0.11; P<0.001). CONCLUSIONS: In asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction undergoing exercise stress echocardiography, a lower % of age-sex-predicted METs and slower heart rate recovery were associated with longer-term mortality, whereas AV replacement was associated with improved survival.

Impact of duration of mitral regurgitation on outcomes in asymptomatic patients with myxomatous mitral valve undergoing exercise stress echocardiography.

BACKGROUND: Significant mitral regurgitation (MR) typically occurs as holosystolic (HS) or mid-late systolic (MLS), with differences in volumetric impact on the left ventricle (LV). We sought to assess outcomes of degenerative MR patients undergoing exercise echocardiography, separated based on MR duration (MLS versus HS). METHODS AND RESULTS: We included 609 consecutive patients with ≥III+myxomatous MR undergoing exercise echocardiography: HS (n=487) and MLS (n=122). MLS MR was defined as delayed appearance of MR signal during mid-late systole on continuous-wave Doppler while HS MR occurred throughout systole. Composite events of death and congestive heart failure were recorded. Compared to MLS MR, HS MR patients were older (60±14 versus 53±14 years), more were males (72% versus 53%), and had greater prevalence of atrial fibrillation (16% versus 7%; all P<0.01). HS MR patients had higher right ventricular systolic pressure (RVSP) at rest (33±11 versus 27±9 mm Hg), more flail leaflets (36% versus 6%), and a lower number of metabolic equivalents (METs) achieved (9.5±3 versus 10.5±3), compared to the MLS MR group (all P<0.05). There were 54 events during 7.1±3 years of follow-up. On step-wise multivariable analysis, HS versus MLS MR (HR 4.99 [1.21 to 20.14]), higher LV ejection fraction (hazard ratio [HR], 0.94 [0.89 to 0.98]), atrial fibrillation (HR, 2.59 [1.33 to 5.11]), higher RVSP (HR, 1.05 [1.03 to 1.09]), and higher percentage of age- and gender-predicted METs (HR, 0.98 [0.97 to 0.99]) were independently associated with adverse outcomes (all P<0.05). CONCLUSION: In patients with ≥III+myxomatous MR undergoing exercise echocardiography, holosystolic MR is associated with adverse outcomes, independent of other predictors.

Outcomes of surgical aortic valve replacement for severe aortic stenosis: Incorporation of left ventricular systolic function and stroke volume index.

OBJECTIVES: We sought to assess predictors of mortality in consecutive patients with severe aortic stenosis undergoing aortic valve replacement and to determine whether there are differences in mortality, separated on the basis of different aortic stenosis subtypes and left ventricular stroke volume index. METHODS: We studied 875 patients (aged 69 ± 12 years, 67% were men) with severe aortic stenosis (aortic valve area ≤ 1 cm(2)) who underwent aortic valve replacement between January 2007 and December 2008 (excluding other severe valve disease, balloon aortic valvuloplasty, and transcatheter aortic valve replacement). Clinical and echocardiographic data were recorded. Left ventricular stroke volume index was measured as left ventricular outflow tract velocity time integral × left ventricular outflow tract area/body surface area. Patients were classified into the following subtypes: (1) standard severe (n = 536, left ventricular ejection fraction ≥ 50% and mean gradient ≥ 40 mm Hg); (2) paradoxic severe (n = 152, left ventricular ejection fraction ≥ 50%, mean gradient <40 mm Hg and left ventricular stroke volume index <35 mL/m(2)); and (3) low left ventricular ejection fraction severe (n = 187, ejection fraction <50%). Society of Thoracic Surgeons score and all-cause mortality were recorded. RESULTS: At 4.8 ± 2 years, 153 patients (18%) died (30-day mortality 1.8%). On multivariable Cox analysis, age (hazard ratio [HR], 1.49), New York Heart Association class (HR, 1.52), prior cardiac surgery (HR, 1.41), aortic stenosis subtypes (standard severe reference HR, 1; paradoxic severe HR, 1.48; and low left ventricular ejection fraction severe HR, 2.03), and reduced glomerular filtration rate (HR, 1.17) were associated with higher long-term mortality (P < .05). CONCLUSIONS: In patients with severe aortic stenosis undergoing aortic valve replacement, patients with standard severe aortic stenosis had better long-term survival than those with paradoxic severe or low left ventricular ejection fraction severe aortic stenosis.

Incremental prognostic value of left ventricular global longitudinal strain in patients with aortic stenosis and preserved ejection fraction.

BACKGROUND: We sought to assess the utility of left ventricular global longitudinal strain (LV-GLS) in predicting mortality in moderate to severe and paradoxical severe aortic stenosis (AS) patients with preserved ejection fraction. METHODS AND RESULTS: We studied 395 AS patients (70 ± 14 years, 57% men) with aortic valve area <1.3 cm(2) evaluated between January to June 2008 (excluding severe other valve disease and LV ejection fraction <50%). Clinical and echocardiographic data were recorded. LV-GLS was analyzed using Velocity Vector Imaging. AS patients were classified as (a) moderate-severe (n=93; aortic valve area, 1.1-1.3 cm(2)), (b) standard severe (n=161; aortic valve area, ≤1 cm(2); mean gradient ≥40 mm Hg), and (c) paradoxical severe (n=141; aortic valve area, ≤1 cm2 and mean gradient <40 mm Hg). Additive Euroscore was 7 ± 3. The association of LV-GLS with all-cause mortality was assessed after risk-adjustment using Cox proportional hazards models. Median LV-GLS was -14.8% (interquartile range, -17.2%, -12.1%). At 4.4±1.4 years, there were 92 (23%) deaths. On multivariable Cox analysis, additive Euroscore (hazard ratio, 1.19; 1.13-1.27; P<0.001), New York Heart Association class (hazard ratio, 1.44; 1.11-1.87; P<0.001), AV surgery with time-dependent covariate analysis (hazard ratio, 0.29; 0.19-0.45; P<0.001), and LV-GLS (hazard ratio, 1.05; 1.03-1.07; P<0.001) were independent predictors of mortality. LV-GLS <-12.1% (4th quartile) was associated with significantly reduced survival. Addition of LV-GLS to clinical parameters (additive Euroscore+New York Heart Association class) led to significant improvement in prediction of mortality (χ(2) increased from 48 to 58; P<0.01). CONCLUSIONS: LV-GLS independently predicts mortality in moderate-severe and severe AS patients with preserved LV ejection fraction, providing incremental prognostic utility, in addition to standard clinical and echocardiographic parameters.

Importance of exercise capacity in predicting outcomes and determining optimal timing of surgery in significant primary mitral regurgitation.

BACKGROUND: In primary mitral regurgitation (MR), exercise echocardiography aids in symptom evaluation and timing of mitral valve (MV) surgery. In patients with grade ≥3 primary MR undergoing exercise echocardiography followed by MV surgery, we sought to assess predictors of outcomes and whether delaying MV surgery adversely affects outcomes. METHODS AND RESULTS: We studied 576 consecutive such patients (aged 57±13 years, 70% men, excluding prior valve surgery and functional MR). Clinical, echocardiographic (MR, LVEF, indexed LV dimensions, RV systolic pressure) and exercise data (metabolic equivalents) were recorded. Composite events of death, MI, stroke, and congestive heart failure were recorded. Mean LVEF was 58±5%, indexed LV end-systolic dimension was 1.7±0.5 mm/m(2), rest RV systolic pressure was 32±13 mm Hg, peak-stress RV systolic pressure was 47±17 mm Hg, and percentage of age- and gender-predicted metabolic equivalents was 113±27. Median time between exercise and MV surgery was 3 months (MV surgery delayed ≥1 year in 28%). At 6.6±4 years, there were 53 events (no deaths at 30 days). On stepwise multivariable survival analysis, increasing age (hazard ratio of 1.07 [95% confidence interval, 1.03 to 1.12], P<0.01), lower percentage of age- and gender-predicted metabolic equivalents (hazard ratio of 0.82 [95% confidence interval, 0.71 to 0.94], P=0.007), and lower LVEF (0.94 [0.89 to 0.99], P=0.04) independently predicted outcomes. In patients achieving >100% predicted metabolic equivalents (n=399), delaying surgery by ≥1 year (median of 28 months) did not adversely affect outcomes (P=0.8). CONCLUSION: In patients with primary MR that underwent exercise echocardiography followed by MV surgery, lower achieved metabolic equivalents were associated with worse long-term outcomes. In those with preserved exercise capacity, delaying MV surgery by ≥1 year did not adversely affect outcomes.