Race, Hypertensive Disorders of Pregnancy and Outcomes in Peripartum Cardiomyopathy.

BACKGROUND: Black women with peripartum cardiomyopathy (PPCM) have a higher prevalence of hypertensive disorders of pregnancy (HDP) and worse clinical outcomes compared with non-Black women. We examined the impact of HDP on myocardial recovery in Black women with PPCM. METHODS: A total of 100 women were enrolled into the Investigation in Pregnancy Associated Cardiomyopathy (IPAC) study. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6, and 12-months post-partum (PP). Women were followed for 12 months postpartum and outcomes including persistent cardiomyopathy (LVEF≤35%), left ventricular assist device, (LVAD), cardiac transplantation, or death were examined in subsets based on race and the presence of HDP. RESULTS: Black women with HDP were more likely to present earlier compared to Black women without HDP (days PP HDP: 34±21 vs 54±27 days, P=0.03). There was no difference in LVEF at study entry for Black women based on HDP, but better recovery with HDP at 6 (HDP:52±11% vs no HDP: 40±14%, P=0.03) and 12-months (HDP:53±10% vs no HDP:40±16%, P=0.02). At 12-months, Black women overall had a lower LVEF than non-Black women (P<0.001), driven by less recovery in Black women without HDP compared to non-Black women (P<0.001). In contrast, Black women with HDP had a similar LVEF at 12 months compared to non-Black women (P=0.56). CONCLUSIONS: In women with PPCM, poorer outcomes evident in Black women were driven by women without a history of HDP. In Black women, a history of HDP was associated with earlier presentation and recovery which was comparable to non-Black women.

Mechanical dyssynchrony as a selection criterion for cardiac resynchronization therapy: Design of the AMEND-CRT trial.

AIMS: One third of patients do not improve after cardiac resynchronization therapy (CRT). Septal flash (SF) and apical rocking (ApRock) are deformation patterns observed on echocardiography in most patients eligible for CRT. These markers of mechanical dyssynchrony have been associated to improved outcome after CRT in observational studies and may be useful to better select patients. The aim of this trial is to investigate whether the current guideline criteria for selecting patients for CRT should be modified and include SF and ApRock to improve therapy success rate, reduce excessive costs and prevent exposure to device-related complications in patients who would not benefit from CRT. METHODS: The AMEND-CRT trial is a multicentre, randomized, parallel-group, double-blind, sham-controlled trial with a non-inferiority design. The trial will include 578 patients scheduled for CRT according to the 2021 ESC guidelines who satisfy all inclusion criteria. The randomization is performed 1:1 to an active control arm ('guideline arm') or an experimental arm ('echo arm'). All participants receive a device, but in the echo arm, CRT is activated only when SF or ApRock or both are present. The outcome of both arms will be compared after 1 year. The primary outcome measures are the average change in left ventricular end-systolic volume and patient outcome assessed using a modified Packer Clinical Composite Score. CONCLUSIONS: The findings of this trial will redefine the role of echocardiography in CRT and potentially determine which patients with heart failure and a prolonged QRS duration should receive CRT, especially in patients who currently have a class IIa or class IIb recommendation.

In vivo fluid dynamics of the Ventura interatrial shunt device in patients with heart failure.

AIMS: Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). METHODS AND RESULTS: Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow-pressure relationship of the shunt. Open-label patients from the RELIEVE-HF trial underwent TEE at shunt implant and at 6 and 12 month follow-up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. Deff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans-shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R2 ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12. CONCLUSIONS: When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.

Association between right ventricular global longitudinal strain and mortality in intermediate-risk pulmonary embolism.

BACKGROUND: Right ventricular (RV) systolic dysfunction has been identified as a prognostic marker for adverse clinical events in patients presenting with acute pulmonary embolism (PE). However, challenges exist in identifying RV dysfunction using conventional echocardiography techniques. Strain echocardiography is an evolving imaging modality which measures myocardial deformation and can be used as an objective index of RV systolic function. This study evaluated RV Global Longitudinal Strain (RVGLS) in patients with intermediate risk PE as a parameter of RV dysfunction, and compared to traditional echocardiographic and CT parameters evaluating short-term mortality. METHODS: Retrospective single center cohort study of 251 patients with intermediate-risk PE between 2010 and 2018. The primary outcome was all-cause mortality at 30 days. Statistical analysis evaluated each parameter comparing survivors versus non-survivors at 30 days. Receiver operating characteristic (ROC) curves and Kaplan-Meier curves were used for comparison of the two cohorts. RESULTS: Altogether 251 patients were evaluated. Overall mortality rate was 12.4%. Utilizing an ROC curve, an absolute cutoff value of 17.7 for RVGLS demonstrated a sensitivity of 93% and specificity of 70% for observed 30-day mortality. Individuals with an RVGLS ≤17.7 had a 25 times higher mortality rate than those with RVGLS above 17.7 (HR 25.24, 95% CI = 6.0-106.4, p < .001). Area under the curve was (.855), RVGLS outperformed traditional echocardiographic parameters, CT findings, and cardiac biomarkers on univariable and multivariable analysis. CONCLUSIONS: Reduced RVGLS values on initial echocardiographic assessment of patients with intermediate-risk PE identified patients at higher risk for mortality at 30 days.

Interatrial shunt therapy in advanced heart failure: Outcomes from the open-label cohort of the RELIEVE-HF trial.

AIMS: Heart failure (HF) outcomes remain poor despite optimal guideline-directed medical therapy (GDMT). We assessed safety, effectiveness, and transthoracic echocardiographic (TTE) outcomes during the 12 months after Ventura shunt implantation in the RELIEVE-HF open-label roll-in cohort. METHODS AND RESULTS: Eligibility required symptomatic HF despite optimal GDMT with ≥1 HF hospitalization in the prior year or elevated natriuretic peptides. The safety endpoint was device-related major adverse cardiovascular or neurological events at 30 days, compared to a prespecified performance goal. Effectiveness evaluations included the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 1, 3, 6, and 12 months and TTE at baseline and 12 months. Overall, 97 patients were enrolled and implanted at 64 sites. Average age was 70 ± 11 years, 97% were in New York Heart Association class III, and half had left ventricular ejection fraction (LVEF) ≤40%. The safety endpoint was achieved (event rate 0%, p < 0.001). KCCQ overall summary score was improved by 12-16 points at all follow-up timepoints (all p < 0.004), with similar outcomes in patients with reduced and preserved LVEF. At 12 months, left ventricular end-systolic and end-diastolic volumes were reduced (p = 0.020 and p = 0.038, respectively), LVEF improved (p = 0.009), right ventricular end-systolic and end-diastolic areas were reduced (p = 0.001 and p = 0.030, respectively), and right ventricular fractional area change (p < 0.001) and tricuspid annular plane systolic excursion (p < 0.001) improved. CONCLUSION: Interatrial shunting with the Ventura device was safe and resulted in favourable clinical effects in patients with HF, regardless of LVEF. Improvements of left and right ventricular structure and function were consistent with reverse myocardial remodelling. These results would support the potential of this shunt device as a treatment for HF.

Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator-activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Junctional AV ablation in patients with atrial fibrillation undergoing cardiac resynchronization therapy (JAVA-CRT): results of a multicenter randomized clinical trial pilot program.

INTRODUCTION: Cardiac resynchronization therapy (CRT) improves outcomes in sinus rhythm, but the data in atrial fibrillation (AF) is limited. Atrio-ventricular junctional ablation (AVJA) has been proposed as a remedy. The objective was to test if AVJA results in LV end-systolic volume (ESV) reduction ≥ 15% from baseline to 6 months. METHODS: The trial was a prospective multicenter randomized trial in 26 patients with permanent AF who were randomized 1:1 to CRT-D with or without AVJA. RESULTS: LVESV improved similarly by at least 15% in 5/10 (50%) in the CRT-D-only arm and in 6/12 (50%) in the AVJA + CRT-D arm (OR = 1.00 [0.14, 7.21], p = 1.00). In the CRT-D-only arm, the median 6-month improvement in LVEF was 9.2%, not different from the AVJA + CRT-D arm, 8.2%. When both groups were combined, a significant increase in LVEF was observed (25.4% at baseline vs 36.2% at 6 months, p = 0.002). NYHA class from baseline to 6 months for all patients combined improved 1 class in 15 of 24 (62.5%), whereas 9 remained in the same class and 0 degraded to a worse class. CONCLUSION: In patients with permanent AF, reduced LVEF, and broad QRS who were eligible for CRT, there was insufficient evidence that AVJA improved echocardiographic or clinical outcomes; the results should be interpreted in light of a smaller than planned sample size. CRT, however, seemed to be effective in the combined study cohort overall, suggesting that CRT can be reasonably deployed in patients with AF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02946853.

Prognostic significance of longitudinal strain in dilated cardiomyopathy with recovered ejection fraction.

OBJECTIVE: Patients 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). METHODS: We designed a retrospective, international, longitudinal cohort study enrolling patients with NICM with LVEF <40% improved to the normal range (>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. RESULTS: 206 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 <16%, respectively. During a follow-up of 5.5±2.8 years, 35 patients (17%) died. aGLS at the time of first recording of a recovered LVEF correlated with mortality during follow-up (HR 0.90, 95% CI 0.91 to 0.99, p=0.048 in adjusted Cox model). No deaths were observed in patients with normal aGLS (>18%). In unadjusted Kaplan-Meier survival analysis, aGLS <16% was associated with higher mortality during follow-up (31 deaths (22%) in patients with GLS <16% vs 4 deaths (6.2%) in patients with GLS ≥16%, HR 3.2, 95% CI 1.1 to 9, p=0.03). CONCLUSIONS: In patients with NICM and normalised LVEF, an impaired aGLS at the time of LVEF recovery is frequent and associated with worse outcomes.

Echocardiographic and clinical predictors of cardiac amyloidosis: limitations of apical sparing.

AIMS: The accuracy of an apical-sparing strain pattern on transthoracic echocardiography (TTE) for predicting cardiac amyloidosis (CA) has varied in prior studies depending on the underlying cohort. We sought to evaluate the performance of apical sparing and other TTE strain findings to screen for CA in an unselected population and determine the frequency that patients with echocardiographic concern for CA undergo evaluation for amyloidosis in clinical practice. METHODS AND RESULTS: As strain is routinely performed at our institution on all clinical TTEs, we identified all TTEs performed from 2016 through 2019 with reported concern for CA or apical sparing. We determined the performance characteristics for echocardiographic strain findings in discriminating CA including apical sparing, the ejection fraction to global longitudinal strain ratio (EF/GLS), and the septal apical-septal basal ratio (SA/SB); other clinical predictors of confirmed CA; and predictors of patients who underwent complete evaluation for CA. CA was confirmed by endomyocardial biopsy or diagnostic cardiac imaging. A total of 547 TTEs, representing 451 patients, reported concern for CA and had adequate strain for analysis. A total of 111 patients underwent complete evaluation for amyloidosis with 100 patients undergoing complete cardiac evaluation for CA. In those 100 patients, multivariable predictors of confirmed CA were age [odds ratio (OR) 3.37 per 5 years], a visual apical-sparing pattern (OR 10.85), and left ventricular ejection fraction (LVEF)/GLS > 4.1 (OR 35.37). CA was less likely in those with coronary artery disease (OR 0.04), hypertension (OR 0.18), and increased systolic blood pressure (OR 0.60 per 5 mm Hg increase). SA/SB [area under the curve (AUC) 0.72, 95% confidence interval (CI) 0.60-0.84] and LVEF/GLS (AUC 0.72, 95% CI 0.60-0.84) both had improved discrimination for CA compared with the apical-sparing ratio (AUC 0.66, 95% CI 0.54-0.79). Many patients with suggestive TTE findings did not receive an evaluation for amyloidosis. Complete evaluation was more likely with Caucasian race (OR 2.1), increased septal thickness (OR 1.4), increased body mass index (OR 1.2), and if the report specifically stated 'amyloid' (OR 1.9). Evaluations were less likely in patients with comorbidities. While hypertension reduced the likelihood of evaluating for CA, 34% of patients with CA had hypertension (>130/80 mm Hg) at time of diagnosis. CONCLUSIONS: In a broad population of patients undergoing TTE, apical sparing on strain imaging increased the likelihood of CA diagnosis but with modest sensitivity and specificity. GLS/EF ratio may be a more reliable tool to screen for CA. The low rate of complete evaluation in patients with concerning TTE findings indicates a strong need for practice improvement and enhanced disease awareness.

Left bundle branch block without a typical contraction pattern is associated with increased risk of ventricular arrhythmias in cardiac resynchronization therapy patients.

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.

Interim Analysis of the Phase II Study: Noninferiority Study of Doxorubicin with Upfront Dexrazoxane plus Olaratumab for Advanced or Metastatic Soft-Tissue Sarcoma.

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.

Prognostic Utility of Echocardiographic Atrial and Ventricular Strain Imaging in Patients With Cardiac Amyloidosis.

OBJECTIVES: The prognostic value of echocardiographic atrial and ventricular strain imaging in patients with biopsy-proven cardiac amyloidosis was assessed. BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

The Prognostic Value of Right Atrial Strain Imaging in Patients with Precapillary Pulmonary Hypertension.

BACKGROUND: 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. METHODS: 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 pressure < 15 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. RESULTS: 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. CONCLUSIONS: 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.