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Purpose: To report the interim analysis of the phase II single-arm noninferiority trial, testing the upfront use of dexrazoxane with doxorubicin on progression-free survival (PFS) and cardiac function in soft-tissue sarcoma (STS). Patients and Methods: Patients with metastatic or unresectable STS who were candidates for first-line treatment with doxorubicin were deemed eligible. An interim analysis was initiated after 33 of 65 patients were enrolled. Using the historical control of 4.6 months PFS for doxorubicin in the front-line setting, we tested whether the addition of dexrazoxane affected the efficacy of doxorubicin in STS. The study was powered so that a decrease of PFS to 3.7 months would be considered noninferior. Secondary aims included cardiac-related mortality, incidence of heart failure/cardiomyopathy, and expansion of cardiac monitoring parameters including three-dimensional echocardiography. Patients were allowed to continue on doxorubicin beyond 600 mg/m2 if they were deriving benefit and were not demonstrating evidence of symptomatic cardiac dysfunction. Results: At interim analysis, upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 8.4 months (95% confidence interval: 5.1–11.2 months). Only 3 patients were removed from study for cardiotoxicity, all on > 600 mg/m2 doxorubicin. No patients required cardiac hospitalization or had new, persistent cardiac dysfunction with left ventricular ejection fraction remaining below 50%. The median administered doxorubicin dose was 450 mg/m2 (interquartile range, 300–750 mg/m2). Conclusions: At interim analysis, dexrazoxane did not reduce PFS in patients with STS treated with doxorubicin. Involvement of cardio-oncologists is beneficial for the monitoring and safe use of high-dose anthracyclines in STS. See related commentary by Benjamin and Minotti, p. 3809

Objectives This study sought to test the hypothesis that speckle tracking strain echocardiography can quantify neurocardiac injuries in patients with aneurysmal subarachnoid hemorrhage (SAH), which is associated with worse clinical outcome. Background SAH may be a life-threatening disease associated with variable degrees of neurocardiac injury. Strain imaging has the potential to detect subtle myocardial dysfunction which is additive to conventional measurements. Methods A total of 255 consecutive patients were prospectively enrolled with acute SAH, who were admitted to the intensive care unit with echocardiography studies within 72 h. Left ventricular (LV) and right ventricular (RV) strains were acquired from standard apical views. Abnormal LV global longitudinal strain (GLS) and RV free-wall strain were pre-defined as Results Performing LV GLS was feasible in 221 patients (89%) 53 ± 10 years of age, 71% female, after excluding those with previous cardiac disease. Abnormal LV GLS findings were observed in 53 patients (24%) and were associated with worse clinical severity, including a Hunt-Hess grade >3 (34% vs. 15%; p = 0.005) and biomarker evidence of neurocardiac injury and higher troponin values (1.50 [interquartile range (IQR): 0.01 to 3.87] vs. 0.01 [IQR: 0.01 to 0.22] ng/ml; p Conclusions Neurocardiac injury can be detected by LV GLS and RV strain in patients with acute SAH. LV GLS was significantly associated with in-hospital mortality. RV strain, when available, added prognostic value to LV GLS. Abnormal myocardial strain is a marker for increased risk of in-hospital mortality in SAH and has clinical prognostic utility.

Coronary artery disease is the most frequently cause of malignant arrhythmias and sudden cardiac death (SCD), but SCD can also origin from nonischemic cardiomyopathies. Left ventricular ejection fraction (LVEF) has obvious shortcomings as a predictor of patients at risk for implantable cardioverter defibrillator placement and SCD. Mechanical dispersion is a measure of heterogeneous ventricular contraction patterns and has the ability to predict ventricular arrhythmias. The temporal aspects of strain and strain-rate curves also provide insights into the electromechanical substrate of response to cardiac resynchronization therapy, left bundle branch block, myocardial scar, and other features confounding the relationship between changing left ventricular (LV) activation patterns and ventricular response. This chapter presents the use of strain parameters that record the timing of LV contraction in the management of patients with ischemic and nonischemic cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a serious complication of pregnancy associated with variable degrees of left ventricular (LV) recovery. The aim of this study was to test the hypothesis that global LV strain at presentation has prognostic value in patients with PPCM. METHODS: One hundred patients with PPCM aged 30 ± 6 years were enrolled in the multicenter Investigation in Pregnancy Associated Cardiomyopathy study along with 21 normal female control subjects. Speckle-tracking global longitudinal strain (GLS) and global circumferential strain (GCS) analysis was performed. The predefined primary combined outcome variable was death, transplantation, LV assist device implantation, or evidence of persistent LV dysfunction (LV ejection fraction [LVEF] < 50%) at 1 year. RESULTS: GLS measurement was feasible in 110 subjects: 89 of 90 patients with PPCM (99%) with echocardiographic data and all 21 control subjects. Of 84 patients (94%) with 1-year follow-up, 21 (25%) had unfavorable primary outcomes: four LV assist device placements, two deaths, and 15 patients with persistent LV dysfunction. GLS at presentation with a cutoff of 10.6% (absolute value) was specifically associated with the subsequent primary outcome with 75% sensitivity and 95% specificity. GCS at presentation with a cutoff of 10.1% was associated with the primary outcome with 78% sensitivity and 84% specificity. GLS and GCS remained significantly associated with outcomes after adjusting for LVEF (GLS odds ratio, 2.07; P < .001; GCS odds ratio, 1.37; P = .005). GLS was significantly additive to LVEF (C statistic = 0.76–0.91, net reclassification improvement = 1.32, P < .001). CONCLUSIONS: GLS and GCS in patients with PPCM at presentation were associated with subsequent clinical outcomes, including death, LV assist device implantation, and evidence of persistent LV dysfunction. Strain measures may add prognostic information over LVEF for risk stratification.

Introduction: Peripartum cardiomyopathy (PPCM) is a rare form of pregnancy-related heart failure associated with preeclampsia. Our understanding of their shared pathophysiology is limited as are treatment options. Hypothesis: We hypothesized that plasma proteomic profiling would identify deleterious circulating proteins and provide insights into shared mechanisms driving preeclampsia and PPCM. Methods: We performed serum proteomic case-control studies in women with preeclampsia or PPCM to identify biological processes common to both conditions. The top candidate was validated in independent preeclampsia (n=58) and PPCM (n=114) cohorts. Preeclamptic placenta was examined as a potential source of circulating proteins. Therapeutic targeting the top candidate was examined in an animal model of PPCM. Results: Paradoxically, we found the senescence-associated secretory phenotype (SASP), a marker of biological aging, to be the most upregulated process in relatively young women with preeclampsia (normalized enrichment score [NES]=3.3;p adj =4.0x10 -6 ) or PPCM (NES=3.2;p adj =1.9x10 -5 ). 28 circulating proteins contributed to this common signal, and were strongly enriched in preeclamptic placenta, which expressed markers of increased senescence. The TGFb family member, Activin-A, was the most highly upregulated SASP gene in preeclamptic placentas (5-fold;p Conclusions: These data implicate placental senescence in the increased deleterious circulating proteins seen in preeclampsia and PPCM. We identify multiple new circulating factors associated with these diseases and demonstrate that targeting SASP proteins, such as Activin-A, can mitigate PPCM in mice.

Cardiac resynchronization therapy (CRT) reduces the risk of ventricular arrhythmias (VA) in heart failure (HF) patients with left bundle branch block (LBBB) while the effect is less clear among non-LBBB patients. This study aimed to investigate if absence of LBBB features whether by echocardiography or strict ECG criteria would identify patients at risk of developing VA in a cohort with LBBB according to conventional ECG criteria. Two hundred six CRT candidates were prospectively included from 2 centers. Prior to CRT presence of a typical LBBB contraction pattern was identified using longitudinal strain in the apical 4-chamber view. All preimplantation ECGs were categorized as LBBB or non-LBBB according to Strauss´ strict criteria. Primary end-point was defined as any appropriate antitachycardia pacing (ATP) or shock therapy within 2 years after CRT implantation. A total of 129 (63%) patients had a typical LBBB contraction pattern, while 134 (66%) met the strict ECG criteria. Over 2 years, 45 patients (22%) experienced VA. Absence of a typical LBBB contraction pattern was independently associated with an increased risk of VA (hazard ratio ([HR] 1.89; 95% CI 1.04 to 3.44; p: 0.036). Strict LBBB was not independently associated with the occurrence of VA. Fulfilling neither strict ECG nor echocardiographic criteria for LBBB was associated with a 3.3-fold increase in risk of VA ([HR] 3.34; 95% CI 1.75 to 6.94; (p < 0.001). The risk of VA was almost 2-fold higher if a typical LBBB contraction pattern was absent prior to CRT.

OBJECTIVES In this study, the authors tested the hypotheses that the systolic stretch index (SSI) developed by computer modeling and applied using echocardiographic strain imaging may characterize the electromechanical substrate predictive of outcome following cardiac resynchronization therapy (CRT). They included patients with QRS width 120 to 149 ms or non-left bundle branch block (LBBB), where clinical uncertainty for CRT exists. They further tested the hypothesis that global longitudinal strain (GLS) has additional prognostic value.BACKGROUND Response to CRT is variable. Guidelines favor patient selection by electrocardiographic LBBB with QRS width >= 150 ms.METHODS The authors studied 442 patients enrolled in the Adaptive CRT 94-site randomized trial with New York Heart Association functional class III-IV heart failure, ejection fraction = 120 ms. A novel computer program semiautomatically calculated the SSI from strain curves as the sum of posterolateral prestretch percent before aortic valve opening and the septal rebound stretch percent during ejection. The primary endpoint was hospitalization for heart failure (HF) or death, and the secondary endpoint was death over 2 years after CRT.RESULTS In all patients, high longitudinal SSI (>= group median of 3.1%) was significantly associated with freedom from the primary endpoint of HF hospitalization or death (hazard ratio [HR] for low SSI: 2.17; 95% confidence interval [CI]: 1.45 to 3.24, p = group median of 2.6%) had significantly fewer HF hospitalizations or deaths (HR for low SSI: 2.08; 95% CI: 1.27 to 3.41, p = 0.004) and longer survival (HR for low SSI: 5.08; 95% CI: 1.94 to 13.31, p = 150 ms. SSI by circumferential strain had similar associations with clinical outcomes, and GLS was additive to SSI in predicting clinical events (p = 0.001).CONCLUSIONS Systolic stretch by strain imaging characterized the myocardial substrate associated with favorable CRT response, including in the important patient subgroup with QRS width 120 to 149 ms or non-LBBB. GLS had additive prognostic value. (C) 2019 by the American College of Cardiology Foundation.

ObjectivePatients with non-ischaemic dilated cardiomyopathy (NICM) may experience a normalisation in left ventricular ejection fraction (LVEF). Although this correlates with improved prognosis, it does not correspond to a normalisation in the risk of death during follow-up. Currently, there are no tools to risk stratify this population. We tested the hypothesis that absolute global longitudinal strain (aGLS) is associated with mortality in patients with NICM and recovered ejection fraction (LVEF).MethodsWe designed a retrospective, international, longitudinal cohort study enrolling patients with NICM with LVEF 50%). We studied the relationship between aGLS measured at the time of the first recording of a normalised LVEF and all-cause mortality during follow-up. We considered aGLS >18% as normal and aGLS ≥16% as of potential prognostic value.Results206 patients met inclusion criteria. Median age was 53.5 years (IQR 44.3–62.8) and 56.6% were males. LVEF at diagnosis was 32.0% (IQR 24.0–38.8). LVEF at the time of recovery was 55.0% (IQR 51.7–60.0). aGLS at the time of LVEF recovery was 13.6%±3.9%. 166 (80%) and 141 (68%) patients had aGLS ≤18% and 18%). In unadjusted Kaplan-Meier survival analysis, aGLS ConclusionsIn patients with NICM and normalised LVEF, an impaired aGLS at the time of LVEF recovery is frequent and associated with worse outcomes.

Introduction: Myofibril deposition in amyloidosis diffusely may affect cardiac structure and function. Right ventricular involvement has been associated with adverse clinical outcome. However, the utility of right atrial (RA) function assessment by echocardiographic strain imaging is unclear. Hypothesis: We hypothesize that right atrial stain has prognostic value in cardiac amyloidosis. Methods: We studied 121 consecutive patients with cardiac amyloidosis: 18% had transthyretin and 79% had light chain amyloidosis. Cardiac amyloidosis was either confirmed by endocardial biopsy (36%) or by a combination of non-cardiac tissue biopsy and proof of left ventricular hypertrophy (64%). Speckle tracking peak RA reservoir strain was assessed based on 6 segments from the apical 4-chamber view. All-cause mortality was tracked over a median of 5 years. Results: Echocardiographic peak longitudinal RA strain was feasible in 109 patients (90%). 60 CA patients died during follow-up period. Peak longitudinal RA strain was reduced in cardiac amyloidosis non-survivors (8.1%) in comparison to survivors (18.3%, p Conclusions: Reduced peak longitudinal RA strain was significantly associated with survival in patients with cardiac amyloidosis. RA reservoir function assessed by strain appears to be useful as a new means to predict prognosis in cardiac amyloidosis patients and has promise for clinical application.

Introduction: Light chain cardiac amyloidosis (AL) has a variable but usually poor prognosis. Left ventricular (LV) function measures including LV strain imaging for global longitudinal strain (GLS) have shown clinically prognostic value in AL. However, the utility of novel left atrial (LA) strain imaging and its associations with LV disease remains unclear. Hypothesis: LA strain is of additive prognostic value to GLS in AL. Methods: We included 99 consecutive patients with AL. Cardiac amyloidosis either confirmed by endocardial biopsy (25%) or by non-cardiac tissue biopsy and imaging data supportive of cardiac amyloidosis. Peak LA reservoir strain was calculated as an average of peak longitudinal strain from apical 2- and 4-chamber views. GLS and apical sparing ratio were assessed using the 3 standard apical views. All-cause mortality was tracked over a median of 5 years. Results: Echocardiographic GLS and peak longitudinal LA strain were feasible in 96 (97%) and 86 (87%) of patients, respectively. There were 48 AL patients who died during follow-up. Patients with low GLS (GLS < median; 10.3% absolute values) had worse prognosis than patients with high GLS group (p Conclusions: Peak longitudinal LA strain was additive to LV GLS in predicting prognosis in patients with biopsy confirmed AL amyloidosis. LA strain imaging has potential clinical utility in patients with AL cardiac amyloidosis.

Introduction: Little is known about global and segmental atrial function in cardiac amyloidosis. Atrial function plays an important role to maintain adequate ventricular filling. Hypothesis: We hypothesized left atrial (LA) and right atrial (RA) segmental strain analysis is prognostic in patients with cardiac amyloidosis. Methods: We studied 121 patients with biopsy-proven cardiac amyloidosis and speckle-tracking strain echocardiography. The LA and RA were divided into 6 segments each (basal, mid, and apical segments of free wall and septum). We determined LA and RA free wall/septal wall peak strain ratios. The primary outcome was all-cause mortality (median follow-up; 5.0 years). Results: Regional LA strain analysis was feasible in 104 patients (86%) and RA in 92 patients (76%). Average LA global peak strain was 18.3±12.1% and RA global peak strain was 20.0±15.0%. We compared LA and RA strain free wall and septal wall segments. Atrial septal strain was significantly reduced compared to free wall strain in RA (10.8±9.9 % vs 30.7± 23.8%, p< 0.01). Free wall/septal wall strain ratio of LA was significantly reduced compared with the ratio of RA (p< 0.01). During the follow up, 60 patients died. All atrial regions showed reduction in peak strain in non-survivors compared with survivors. When dividing patients into 2 groups using LA free wall strain and RA free wall strain median values, low atrial free wall strain was associated with worse prognosis (Log-rank p < 0.001, HR 4.9, 95% CI= 2.6-9.3). Conclusions: LA and RA atrial strain have significant prognostic value in patients with cardiac amyloidosis. Free wall/septal wall strain ratio in LA was significantly reduced compared with RA. Assessment of atrial dysfunction has promise for clinical applications cardiac amyloidosis patients.

Introduction: Guidelines favor patient selection by left bundle branch block (LBBB) with QRS width ≥150 ms for cardiac resynchronization therapy (CRT). Predicting CRT response in patients with QRS width 120 to 149 ms or non-LBBB remains difficult. Left ventricular (LV) global longitudinal strain (GLS) and systolic stretch index (SSI) have shown to characterize the ventricular substrate responsive to CRT. However, the potential application of longitudinal left atrial (LA) strain remains unclear. Hypothesis: Baseline LA strain has prognostic value in CRT patients with intermediate ECG criteria. Methods: We studied 195 patients who underwent CRT based on routine indications: ejection fraction ≤35% and QRS width ≥120 ms. GLS was assessed using the 3 standard apical views. Radial SSI was derived from the mid LV short axis view. Peak longitudinal LA strain was derived from the 2 and 4-chamber apical view. The predefined combined clinical endpoint was death, heart transplant or left ventricular assist device over 4 years after CRT. Results: LA strain was feasible in 162 (83%) of the CRT candidates: QRS duration 156 ± 26 ms, 39.5% had LBBB with QRS ≥ 150ms, 60.5% had intermediate ECG criteria. High peak longitudinal strain (>median, 10.1%) was associated with favorable event-free survival (pmedian, 8.4%) had similar outcome to those with Class I indications for CRT. Multivariable analysis revealed that LA strain had independent prognostic value (hazard ratio 0.9 per LA strain %, p < 0.001) even after adjusted for other clinical, electrophysiological and echocardiographic covariates including QRS morphology and duration, GLS and SSI. Conclusions: Peak LA strain had important prognostic value in candidates for CRT. Prognostic value of LA strain was additive to LV strain characteristics and most significant in CRT patients with intermediate ECG criteria for CRT.

The prognostic value of echocardiographic atrial and ventricular strain imaging in patients with biopsy-proven cardiac amyloidosis was assessed.Although left ventricular global longitudinal strain (GLS) is known to be predictive of outcome, the additive prognostic value of left (LA), right atrial (RA), and right ventricular (RV) strain is unclear.One hundred thirty-six patients with cardiac amyloidosis and available follow-up data were studied by endomyocardial biopsy, noncardiac biopsy with supportive cardiac imaging, or autopsy confirmation. One hundred nine patients (80%) had light-chain, 23 (17%) had transthyretin, and 4 (3%) had amyloid A type cardiac amyloidosis. GLS, RV free wall strain, peak longitudinal LA strain, and peak longitudinal RA strain were measured from apical views. Clinical and routine echocardiographic data were compared. All-cause mortality was followed (median 5 years).Strain data were feasible for GLS in 127 (93%), LA strain in 119 (88%), RA strain in 117 (86%), and RV strain in 102 (75%). Strain values from all 4 chambers were significantly associated with survival. Hazard ratio (HR) and 95% confidence interval (CI) for low median strain values were as follows: GLS, HR: 2.3; 95% CI: 1.3 to 3.8 (p 0.01); LA strain, HR: 7.5; 95% CI: 3.8 to 14.7 (p 0.001); RA strain, HR: 3.5; 95% CI: 2.0 to 6.2 (p 0.001); and RV free wall strain, HR: 2.8; 95% CI: 1.5 to 5.1 (p 0.001). Peak longitudinal LA strain and RV strain remained independently associated with survival in multivariable analysis. Peak LA strain had the strongest association with survival (p 0.001), and LA strain combined with GLS and RV free wall strain had the highest prognostic value (p 0.001).Strain data from all 4 chambers had important prognostic associations with survival in patients with biopsy-confirmed cardiac amyloidosis. Peak longitudinal LA strain was particularly associated with prognosis. Atrial and ventricular strain have promise for clinical utility.

Background Guidelines favor patient selection by left bundle branch block (LBBB) with QRS width ≥150 ms for cardiac resynchronization therapy (CRT). However, predicting response to CRT patients with QRS width 120 to 149 ms or non-LBBB remains difficult. Speckle tracking left atrial (LA) strain is a novel means to assess cardiac function, however its applications to CRT patients remains unclear. Purpose To test the hypothesis that baseline LA strain has prognostic value in CRT patients with intermediate ECG criteria. Methods We studied 195 patients with heart failure (HF) who underwent CRT based on routine indications: ejection fraction ≤35% and QRS width ≥120 ms. GLS was assessed using the 3 standard apical views. LA longitudinal strain was based on 12 segments from the 2 and 4-chamber apical view. Peak LA strain, a measure associated with the reservoir function of the LA, was defined as the average of peak longitudinal strain from all segments. The predefined combined clinical endpoint was death, heart transplant or left ventricular assist device (LVAD) over 4 years after CRT. Results LA strain was feasible in 162 (83%) of the candidates for CRT: age 64±11 years, 72% male, QRS duration 156±26 ms, 39.5% had LBBB with QRS ≥150ms, 60.5% had intermediate ECG criteria. Median LA strain was 11.0% [1.3% - 36.8%]. High LA peak strain was associated with more favorable event-free survival and Low LA Peak strain was associated with worse clinical outcome following CRT (FIGURE, p Conclusions Baseline peak LA strain had important prognostic value in HF patients who are candidates for CRT. Prognostic value of LA strain was most significant in CRT patients with intermediate ECG criteria (QRS 120 to 149ms or non-LBBB) and has promise for clinical applications. LA strain and clinical outcome after CRT Funding Acknowledgement Type of funding source: None

Balloon aortic valvuloplasty (BAV) is used in high-risk patients with severe aortic stenosis (AS) when the benefit of transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) is unclear. Our objective was to identify clinical or echocardiographic features that identify patients likely to benefit from BAV.We studied 141 consecutive patients who underwent BAV from July, 2011 to October, 2017. Clinical characteristics, routine echocardiographic parameters, and speckle tracking imaging of global longitudinal strain (GLS) were assessed before and after BAV. The primary outcome was all-cause mortality as ascertained by the National Death Index.There were 141 patients, median age, 80 years (interquartile range [IQR], 74-87 years) with severe AS (median aortic valve area, 0.66 cm²; IQR, 0.53-0.79 cm²) and median mean gradient of 36 mm Hg (IQR, 27-48 mm Hg) who underwent BAV. The 1-year mortality rate was 52%. Characteristics associated with survival were New York Heart Association class I symptoms, lower brain natriuretic peptide level, higher left ventricular ejection fraction (LVEF)53%, and higher GLS (13.2%; absolute values were used for GLS). Landmark analysis at 60 days showed the 47 patients who underwent TAVR/SAVR after BAV had significantly better 1-year survival than those who did not (P.001).A high 1-year mortality rate was observed in severe AS patients selected for BAV. LVEF and left ventricular (LV)-GLS offer similar prognostic value for 1-year mortality; however, LV-GLS may have potentially increased clinical utility, as it provides a clear threshold for predicting poor outcomes compared with LVEF. As patients who undergo TAVR/SAVR have markedly improved mortality, careful consideration should be given to advance definitive valve therapy in carefully selected BAV patients.

Background Timely recognition of cardiac amyloidosis is clinically important, but the diagnosis is frequently delayed. Objectives We sought to identify a multi-modality approach with the highest diagnostic accuracy in patients evaluated by cardiac biopsy, the diagnostic gold standard. Methods Consecutive patients (N = 242) who underwent cardiac biopsy for suspected amyloidosis within an 18-year period were retrospectively identified. Cardiac biomarker, ECG, and echocardiography results were examined for correlation with biopsy-proven disease. A prediction model for cardiac amyloidosis was derived using multivariable logistic regression. Results The overall cohort was characterized by elevated BNP (median 727 ng/mL), increased left ventricular wall thickness (IWT; median 1.7 cm), and reduced voltage-to-mass ratio (median 0.06 mm/[g/m2]). One hundred and thirteen patients (46%) had either light chain (n = 53) or transthyretin (n = 60) amyloidosis by cardiac biopsy. A prediction model including age, relative wall thickness, left atrial pressure by E/e’, and low limb lead voltage ( Conclusion Among patients with an advanced infiltrative cardiomyopathy phenotype, traditional biomarker, ECG, and echocardiography-based screening tests have limited individual diagnostic utility for cardiac amyloidosis. A prediction algorithm including age, relative wall thickness, E/e’, and low limb lead voltage improves the detection of cardiac biopsy-proven disease.

Circulating microRNAs (c-miRNAs), plasma-based noncoding RNAs that control posttranscriptional gene expression, mediate processes that underlie phenotypical plasticity to exercise. The relationship and biological relevance between c-miRNA expression and variable dose exercise exposure remains uncertain. We hypothesized that certain c-miRNAs respond to changes in exercise intensity and/or duration in a dose-dependent fashion. Muscle release of such c-miRNAs may then deplete intracellular stores, thus facilitating gene reprogramming and exercise adaptation. To address these hypotheses, healthy men participated in variable intensity ( n = 12, 30 × 1 min at 6, 7, and 8 miles/h, order randomized) and variable duration ( n = 14, 7 × 1 mile/h for 30, 60, and 90 min, order randomized) treadmill-running protocols. Muscle-enriched c-miRNAs (i.e., miRNA-1 and miRNA-133a) and others with known relevance to exercise were measured before and after exercise. c-miRNA responses followed three profiles: 1) nonresponsive (miRNA-21 and miRNA-210), 2) responsive to exercise at some threshold but without dose dependence (miRNA-24 and miRNA-146a), and 3) responsive to exercise with dose dependence to increasing intensity (miRNA-1) or duration (miRNA-133a and miRNA-222). We also studied aerobic exercise-trained mice, comparing control, low-intensity (0.5 km/h), or high-intensity (1 km/h) treadmill-running protocols over 4 wk. In high- but not low-intensity-trained mice, we found increased plasma c-miR-133a along with decreased intracellular miRNA-133a and increased serum response factor, a known miR-133a target gene, in muscle. Characterization of c-miRNAs that are dose responsive to exercise in humans and mice supports the notion that they directly mediate physiological adaptation to exercise, potentially through depletion of intracellular stores of muscle-specific miRNAs. NEW & NOTEWORTHY In this study of humans and mice, we define circulating microRNAs in plasma that are dose responsive to exercise. Our data support the notion that these microRNAs mediate physiological adaptation to exercise potentially through depletion of intracellular stores of muscle-specific microRNAs and releasing their inhibitory effects on target gene expression.

Right ventricular (RV) failure in patients with pulmonary hypertension (PH) is associated with unfavorable clinical events and a poor prognosis. Elevation of right atrial (RA) pressure is established as a marker for RV failure. However, the additive prognostic value of RA mechanical function is unclear.The authors tested the hypothesis that RA function by strain echocardiography has prognostic usefulness by studying 165 consecutive patients with precapillary PH defined invasively: mean pulmonary artery pressure ≥ 25 mm Hg and pulmonary capillary wedge pressure15 mm Hg. Speckle-tracking strain analyses of the right atrium and right ventricle were performed, along with routine measures. Peak RA strain values from six segments using generic speckle-tracking software were averaged to RA peak longitudinal strain, representing RA global reservoir function. The primary end point was all-cause mortality during 5 years of follow-up. RA strain was similarly analyzed in a control group of 16 normal subjects for comparison.There were 151 patients with PH (mean age, 55 ± 16 years; 73% women; mean World Health Organization functional class, 2.6 ± 0.6), after 14 exclusions (three with atrial septal defects and 11 with left ventricular ejection fractions 50%). RA strain measurement was feasible in 93% of patients and RV strain measurement in 88%. RA peak longitudinal strain was significantly reduced in patients with PH compared with control subjects, as expected (P .001). During 5-year follow-up, 73 patients (48%) died. Patients with RA peak strain in the lowest quartile (25%) had a significant risk for death (P = .006), even after correcting for confounding variables. RA strain was independently associated with survival in multivariate analysis (P = .039) and had additive prognostic value to RV strain (log-rank P = .01) in subgroup analysis.RA peak longitudinal strain had additive prognostic usefulness to other clinical measures, including RV strain, RA area, and RA pressure, in patients with PH. RA mechanical function by strain imaging has potential for clinical applications in patients with PH.

Diagnosis, prognosis, treatment, and development of new therapies for diseases or syndromes depend on a reliable means of identifying phenotypes associated with distinct predictive probabilities for these various objectives. Left ventricular ejection fraction (LVEF) provides the current basis for combined functional and structural phenotyping in heart failure by classifying patients as those with heart failure with reduced ejection fraction (HFrEF) and those with heart failure with preserved ejection fraction (HFpEF). Recently the utility of LVEF as the major phenotypic determinant of heart failure has been challenged based on its load dependency and measurement variability. We review the history of the development and adoption of LVEF as a critical measurement of LV function and structure and demonstrate that, in chronic heart failure, load dependency is not an important practical issue, and we provide hemodynamic and molecular biomarker evidence that LVEF is superior or equal to more unwieldy methods of identifying phenotypes of ventricular remodeling. We conclude that, because it reliably measures both left ventricular function and structure, LVEF remains the best current method of assessing pathologic remodeling in heart failure in both individual clinical and multicenter group settings. Because of the present and future importance of left ventricular phenotyping in heart failure, LVEF should be measured by using the most accurate technology and methodologic refinements available, and improved characterization methods should continue to be sought.

Background Among various cardiac autoantibodies (AAbs), those recognizing the β 1 -adrenergic receptor (β 1 AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption. Objectives The goal of this study was to investigate the role of β 1 AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy. Methods Peripheral blood samples were drawn at enrollment in patients with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; 1 AR-AAb was determined, and echocardiograms were assessed, at baseline and 6 months. Patients were followed up for ≤48 months. Results Among the 353 patients who had blood samples adequate for the analysis, 62 (18%) were positive for IgG3-β 1 AR-AAbs (IgG3 group), 58 (16%) were positive for IgG but not IgG3 (non-IgG3 group), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. Left ventricular end-diastolic and end-systolic diameters were significantly larger in the non-IgG3 group compared with the other groups (left ventricular end-diastolic diameter, p 1 AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, β = 0.20, p = 0.01; change in LVEF, β = 0.20, p = 0.008). In patients with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had a lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint. Conclusions IgG3-β 1 AR-AAbs were associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy.

Echocardiographic imaging plays a major role in patient selection for cardiac resynchronization therapy (CRT). One-third of patients do not respond; there is interest in advanced echocardiographic imaging to improve response. Current guidelines favor CRT for patients with electrocardiographic (ECG) QRS width of 150 milliseconds or greater and left bundle branch block. ECG criteria are imperfect; there is interest in advanced echocardiographic imaging to improve patient selection. This discussion focuses on newer echocardiographic methods to improve patient selection, improve delivery, and identify patients at risk for poor outcomes and serious ventricular arrhythmias.

Background Apical sparing by longitudinal strain imaging has reported utility for the diagnosis of cardiac amyloidosis. However, potential differences in the apical sparing pattern in light chain (AL) versus transthyretin (ATTR) amyloidosis in patients with high clinical suspicion for cardiac amyloidosis is not clear. Purpose Our objective was to test the hypothesis that echocardiographic strain imaging could determine differences in patients with clinically suspected AL and ATTR cardiac amyloidosis. Methods We studied 206 patients, aged 64±11, with clinically suspected cardiac amyloidosis. Routine longitudinal strain imaging analyses was performed (EchoPAC, GE Healthcare) with bulls-eye plots. After 27 exclusions (8 arrhythmia/frame rate, 19 missing/poor images), there were 179 patients. Included were 129 patients with cardiac amyloid: 42 by endomyocardial biopsy, 4 by technetium pyrophosphate scan, 65 by non-cardiac biopsy with suggestive cardiac imaging (interventricular septal thickness ≥1.2cm by echocardiography or characteristic cardiac MRI findings), 15 with multiple myeloma and suggestive cardiac imaging, and 3 by autopsy; 50 patients had a negative endomyocardial biopsy or autopsy for cardiac amyloid. The apical sparing ratio by strain imaging was calculated as the (average of apical segments) / (average of mid segments + average of basal segments). Results Cardiac amyloidosis patients were 79% with AL and 21% with ATTR. Applying the previously published apical sparing ratio cut-off of 1.0 for longitudinal strain imaging, sensitivity and specificity were 29% and 78%, respectively, for diagnosis of cardiac amyloidosis. Applying a ratio cut-off of 0.81 improved sensitivity to 72% with specificity of 64% and area under the curve (AUC) of 0.66. Positive and negative predictive values were 85% and 46%, respectively, at this ratio cut-off. The apical sparing ratio was significantly higher in AL and ATTR as compared to the biopsy negative group (p Apical sparing pattern and ratio Conclusions Among patients with high clinical suspicion for cardiac amyloidosis, the apical sparing ratio by echocardiographic strain imaging can demonstrate differences for AL and ATTR cardiac amyloidosis and has potential for clinical utility.

INTRODUCTION Improved understanding of the clinical course of ambulatory advanced chronic systolic heart failure may improve the provision of appropriate care and is central to the design of clinical trials in this population. METHODS Twenty-one implanting ventricular assist device (VAD) centers enrolled 400 subjects in the Registry Evaluation of Vital Information for VADs in Ambulatory Life (REVIVAL), a prospective, observational study in ambulatory, chronic, advanced systolic heart failure, designed to identify a cohort with an approximately 25% 1-year risk of the primary composite outcome of death, urgent transplant, or durable mechanical circulatory support. Inclusion criteria utilized only information collected during routine clinical care. Exclusion criteria identified patients with contraindications to VAD. Study inclusion required at least 1 of 10 high-risk criteria derived from established hospitalization and non-hospitalization markers of increased mortality risk. We evaluated the test performance characteristics of the high-risk criteria. RESULTS Data on 373 subjects evaluable for the primary composite outcome at the 1-year visit are presented. Baseline data were consistent with a less advanced cohort than Medical Arm for Mechanically Assisted Circulatory Support or Risk Assessment (MedaMACS) and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients (ROADMAP). Freedom from the primary composite outcome was 75.9%. Non-hospitalization inclusion criteria identified 89% of patients with events. CONCLUSIONS Using routinely obtained clinical information for enrollment, REVIVAL successfully recruited an ambulatory chronic systolic heart failure cohort with an approximately 25% annual risk of the primary composite outcome. Information from this registry will be relevant to the planning of future trials of earlier VAD use and of other interventions in this population.

Background: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined. Methods: In vitro assessment of BOLA3 regulation and gain- and loss-of-function assays were performed in human pulmonary artery endothelial cells using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was used for lung endothelium-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH. Results: In cultured hypoxic pulmonary artery endothelial cells, lung from human patients with Group 1 and 3 PH, and multiple rodent models of PH, endothelial BOLA3 expression was downregulated, which involved hypoxia inducible factor-2-dependent transcriptional repression via histone deacetylase 1-mediated histone deacetylation. In vitro gain- and loss-of-function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency downregulated the glycine cleavage system protein H, thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction while decreasing angiogenic potential. In vivo, pharmacological knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histological and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation. Conclusions: BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine homeostasis with endothelial metabolic reprogramming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, Fe-S biogenesis, and glycine biology, for diagnostic and therapeutic development., National Institutes of Health (U.S.) (Grant R01 HL124021), National Institutes of Health (U.S.) (Grant HL 122596), National Institutes of Health (U.S.) (Grant HL 138437), National Institutes of Health (U.S.) (Grant UH2 TR002073)

Electromechanical association in a normal heart results in synchronous regional left ventricular (LV) contraction. Differences in the timing of regional contraction may be associated with the failing human heart. Interest in echocardiographic assessment of synchrony began with applications for pacing therapy, in particular cardiac resynchronization therapy (CRT), also known as biventricular pacing. Current clinical practice is to select heart failure patients with reduced ejection fraction by electrocardiographic criteria of QRS complex widening or left bundle branch block morphology. Although CRT often results in improvement in symptoms, LV reverse remodeling, and prolonging life, one-third to one-half of patients do not appear to benefit and are referred to as nonresponders. It was observed that patients with measurable dyssynchrony at baseline before CRT had a much more favorable response to CRT than patients who lacked baseline dyssynchrony. Interest in measuring regional timing of LV contraction with echocardiographic techniques remains high to gain a better understanding of CRT response and prognosis. Tissue Doppler imaging and, in particular, speckle tracking strain measures have been widely utilized. However, the field advanced to reveal that mechanical dyssynchrony was more complicated than originally thought. A more recent understanding of regional myocardial discoordination has emerged as differences in regional contraction from substrates of electrical delay, contractile heterogeneity, and fibrosis or scar. Defining the strain patterns of contraction and stretch appear promising to help identify the electromechanical substrate that is associated with the most favorable outcome after CRT. This chapter will review the progress in understanding of mechanical dyssynchrony, define the current state of the art, and project potential future clinical applications of assessing cardiac synchrony.

Background: Identifying candidates for left ventricular assist device surgery at risk of right ventricular failure remains difficult. The aim was to identify the most accurate predictors of right ventricular failure among clinical, biological, and imaging markers, assessed by agreement of different supervised machine learning algorithms. Methods: Seventy-four patients, referred to HeartWare left ventricular assist device since 2010 in two Italian centers, were recruited. Biomarkers, right ventricular standard, and strain echocardiography, as well as cath-lab measures, were compared among patients who did not develop right ventricular failure (N = 56), those with acute–right ventricular failure (N = 8, 11%) or chronic–right ventricular failure (N = 10, 14%). Logistic regression, penalized logistic regression, linear support vector machines, and naïve Bayes algorithms with leave-one-out validation were used to evaluate the efficiency of any combination of three collected variables in an “all-subsets” approach. Results: Michigan risk score combined with central venous pressure assessed invasively and apical longitudinal systolic strain of the right ventricular–free wall were the most significant predictors of acute–right ventricular failure (maximum receiver operating characteristic–area under the curve = 0.95, 95% confidence interval = 0.91–1.00, by the naïve Bayes), while the right ventricular–free wall systolic strain of the middle segment, right atrial strain (QRS-synced), and tricuspid annular plane systolic excursion were the most significant predictors of Chronic-RVF (receiver operating characteristic–area under the curve = 0.97, 95% confidence interval = 0.91–1.00, according to naïve Bayes). Conclusion: Apical right ventricular strain as well as right atrial strain provides complementary information, both critical to predict acute–right ventricular failure and chronic–right ventricular failure, respectively.