Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy

BackgroundIn patients at risk of cancer therapy-related cardiac dysfunction (CTRCD), initiation of cardioprotective therapy (CPT) is constrained by the low sensitivity of ejection fraction (EF) for minor changes in left ventricular (LV) function. Global longitudinal strain (GLS) is a robust and sensitive marker of LV dysfunction, but existing observational data have been insufficient to support a routine GLS-guided strategy for CPT.ObjectivesThis study sought to identify whether GLS-guided CPT prevents reduction in LVEF and development of CTRCD in high-risk patients undergoing potentially cardiotoxic chemotherapy, compared with usual care.MethodsIn this international, multicenter, prospective, randomized controlled trial, 331 anthracycline-treated patients with another heart failure risk factor were randomly allocated to CPT initiation guided by either ≥12% relative reduction in GLS (n = 166) or >10% absolute reduction of LVEF (n = 165). Patients were followed for EF and development of CTRCD (symptomatic EF reduction of >5% or >10% asymptomatic to <55%) over 1 year.ResultsOf 331 randomized patients, 2 died, and 22 withdrew consent or were lost to follow-up. Among 307 patients (age: 54 ± 12 years; 94% women; baseline LVEF: 59 ± 6%; GLS: –20.6 ± 2.4%) with a median (interquartile range) follow-up of 1.02 years (0.98 to 1.07 years), most (n = 278) had breast cancer. Heart failure risk factors were prevalent: 29% had hypertension, and 13% had diabetes mellitus. At the 1-year follow-up, although the primary outcome of change in LVEF was not significantly different between the 2 arms, there was significantly greater use of CPT, and fewer patients met CTRCD criteria in the GLS-guided than the EF-guided arm (5.8% vs. 13.7%; p = 0.02), and the 1-year EF was 57 ± 6% versus 55 ± 7% (p = 0.05). Patients who received CPT in the EF-guided arm had a larger reduction in LVEF at follow-up than in the GLS-guided arm (9.1 ± 10.9% vs. 2.9 ± 7.4%; p = 0.03).ConclusionsAlthough the change in LVEF was not different between the 2 arms as a whole, when patients who received CPT were compared, those in the GLS-guided arm had a significantly lower reduction in LVEF at 1 year follow-up. Furthermore, GLS-guided CPT significantly reduced a meaningful fall of LVEF to the abnormal range. The results support the use of GLS in surveillance for CTRCD. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes [SUCCOUR]; ACTRN12614000341628)     

Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis

BackgroundThere is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.ObjectivesThis study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.MethodsThis study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.ResultsCases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).ConclusionsGLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.     

Prognostic Value of Left Ventricular Global Longitudinal Strain in Patients With Secondary Mitral Regurgitation

BackgroundLeft ventricular (LV) systolic function may be overestimated in patients with secondary mitral regurgitation (MR) when using LV ejection fraction (EF). LV global longitudinal strain (GLS) is a less load-dependent measure of LV function. However, the prognostic value of LV GLS in secondary MR has not been evaluated.ObjectivesThis study sought to demonstrate the prognostic value of LV GLS over LVEF in patients with secondary MR.MethodsA total of 650 patients (mean 66 ± 11 years of age, 68% men) with significant secondary MR were included. The study population was subdivided based on the LV GLS value at which the hazard ratio (HR) for all-cause mortality was >1 using a spline curve analysis (LV GLS <7.0%, impaired LV systolic function vs. LV GLS ≥7.0%, preserved LV systolic function). The primary endpoint was all-cause mortality.ResultsDuring a median follow-up of 56 (interquartile range: 28 to 106 months) months, 334 (51%) patients died. Patients with a more impaired LV GLS showed significantly higher mortality rates at 1-, 2-, and 5-year follow-up (13%, 23%, and 44%, respectively) when compared with patients with more preserved LV systolic function (5%, 14%, and 31%, respectively). On multivariable analysis, LV GLS <7.0% was associated with increased mortality (HR: 1.337; 95% confidence interval: 1.038 to 1.722; p = 0.024), whereas LVEF ≤30% was not (HR: 1.055; 95% confidence interval: 0.794 to 1.403; p = 0.711).ConclusionsIn patients with secondary MR, impaired LV GLS was independently associated with an increased risk for all-cause mortality, whereas LVEF was not. LV GLS may therefore be useful in the risk stratification of patients with secondary MR.     

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy

BackgroundLeft ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients.ObjectivesThis study aims to evaluate the safety and efficacy of aficamten in patients with oHCM.MethodsPatients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout.ResultsFrom baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: ?40 ± 27 mm Hg, and ?43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (?36 ± 27 mm Hg and ?53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (?6% ± 7.5% and ?12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro–B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms.ConclusionsAficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.     

Ventricular-Arterial Coupling Derived From Proximal Aortic Stiffness and Aerobic Capacity Across the Heart Failure Spectrum

BackgroundVentricular-arterial coupling (VAC) can be evaluated as the ratio between arterial stiffness (pulsed wave velocity [PWV]) and myocardial deformation (global longitudinal strain [GLS]).ObjectivesThis study aimed to evaluate VAC across the spectrum of heart failure (HF).MethodsThe authors introduced a Doppler-derived, single-beat technique to estimate aortic arch PWV (aa-PWV) in addition to tonometry-derived carotid-femoral PWV (cf-PWV). They measured PWVs and GLS in 155 healthy controls, 75 subjects at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 236 patients in stage C heart failure with preserved ejection fraction (HFpEF) (n = 104) or heart failure with reduced ejection fraction (HFrEF) (n = 132). They evaluated peak oxygen consumption and peripheral extraction using combined cardiopulmonary-echocardiography exercise stress.Resultsaa-PWV was obtainable in all subjects and significantly lower than cf-PWV in all subgroups (P < 0.01). PWVs were directly related and increased with age (all P < 0.0001). cf-PWV/GLS was similarly compromised in HFrEF (1.09 ± 0.35) and HFpEF (1.05 ± 0.21), whereas aa-PWV/GLS was more impaired in HFpEF (0.70 ± 0.10) than HFrEF (0.61 ± 0.14; P < 0.01). Stage A-B had values of cf-PWV/GLS and aa-PWV/GLS (0.67 ± 0.27 and 0.48 ± 0.14, respectively) higher than controls (0.46 ± 0.11 and 0.39 ± 0.10, respectively) but lower than stage C (all P < 0.01). Peak arteriovenous oxygen difference (AVO₂diff) was inversely related with cf-PWV/GLS and aa-PWV/GLS (all P < 0.01). Although cf-PWV/GLS and aa-PWV/GLS independently predicted peak VO₂ in the overall population (adjusted R² = 0.33 and R²= 0.36; all P < 0.0001), only aa-PWV/GLS was independently associated with flow reserve during exercise (R² = 0.52; P < 0.0001).ConclusionsAbnormal VAC is directly correlated with greater severity of HF and worse functional capacity. HFpEF shows a worse VAC than HFrEF when expressed by aa-PWV/GLS.     

Cardiac Magnetic Resonance Feature Tracking Global Longitudinal Strain and Prognosis After Heart Transplantation

ObjectivesThis study determined the long-term prognostic significance of GLS assessed using CMR-FT in a large cohort of heart transplant recipients.BackgroundIn heart transplant recipients, global longitudinal strain (GLS) assessed using echocardiography has shown promise in the prediction of clinical outcomes. We hypothesized that CMR feature tracking (CMR-FT) GLS is independently associated with long-term outcomes in heart transplant recipients.MethodsIn a cohort of consecutive heart transplant recipients who underwent routine CMR for clinical surveillance, CMR-FT GLS was calculated from 3 long-axis cine CMR images. Associations between GLS and a composite endpoint of death or major adverse cardiac events (MACE), including retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization, were investigated.ResultsA total of 152 heart transplant recipients (age 54 ± 15 years; 29% women; 5.0 ± 5.4 years after heart transplantation) were included. The median GLS was −11.6% (interquartile range: −13.6% to −9.2%). Over a median follow-up of 2.6 years, 59 recipients reached the composite endpoint. On Kaplan-Meier analyses, recipients with GLS worse than the median had a higher estimated cumulative incidence of the composite endpoint compared with recipients with GLS better than the median (log rank p = 0.004). On multivariate Cox proportional hazards regression, GLS was independently associated with the composite endpoint after adjustment for cardiac allograft vasculopathy, history of rejection, left ventricular ejection fraction (LVEF), right ventricular EF, and presence of myocardial fibrosis, with a hazard ratio of 1.15 for every 1% worsening in GLS (95% confidence interval: 1.06 to 1.24; p < 0.001). Similar results were seen in subgroups of recipients with LVEF >50% and with no myocardial fibrosis. GLS provided incremental prognostic value over other variables in the multivariate model as determined by the log-likelihood chi-squared test.ConclusionsIn a large cohort of heart transplant recipients, CMR-FT GLS was independently associated with the long-term risk of death or MACE.     

Improving the Characterization of Stage A and B Heart Failure by Adding Global Longitudinal Strain

BackgroundCurrent guidelines distinguish stage B heart failure (SBHF) (asymptomatic left ventricular [LV] dysfunction) from stage A heart failure (SAHF) (asymptomatic with heart failure [HF] risk factors) on the basis of myocardial infarction, LV remodeling (hypertrophy or reduced ejection fraction [EF]) or valvular disease. However, subclinical HF with preserved EF may not be identified with these criteria.ObjectivesThe purpose of this study was to assess the prediction of incident HF with global longitudinal strain (GLS) in patients with SAHF and SBHF.MethodsThe authors analyzed echocardiograms (including GLS) in 447 patients (age 65 ± 11 years; 77% male) enrolled in a prospective study of HF in individuals at risk of incident HF, with normal or mildly impaired EF (≥40%). Long-term follow-up was obtained via data linkage. Analysis was performed using a competing risks model.ResultsAfter a median of 9 years of follow-up, 50 (10%) of the 447 patients had new HF admissions, and 87 (18%) died. In multivariable analysis, all imaging variables were independent predictors of HF admissions, including left ventricular ejection fraction (LVEF) (HR: 0.97 [95% CI: 0.94-0.99]), LV mass index (HR: 1.01 [95% CI: 1.00-1.02]), left atrial volume index (HR: 1.02 [95% CI: 1.00-1.05]), and E/e′ (HR: 1.05 [95% CI: 1.01-1.24]), incremental to clinical variables (age and Charlson comorbidity score). However, the addition of GLS provided value incremental to both clinical and other echocardiographic parameters (P = 0.004). Impaired GLS (<18%) (HR: 4.09 [95% CI: 1.87-8.92]) was independent and incremental to all clinical and other echocardiographic variables in predicting HF, and impaired LVEF, left ventricular hypertrophy, left atrial enlargement, high E/e′, or SBHF were not predictive.ConclusionsThe inclusion of GLS as a criterion for SBHF would add independent and incremental information to standard markers of SBHF for the prediction of subsequent HF admissions.     

Diagnostic and Prognostic Value of Myocardial Work Indices for Identification of Cancer Therapy–Related Cardiotoxicity

BackgroundEchocardiographic global longitudinal strain (GLS) is a useful measure for detection of cancer treatment–related cardiac dysfunction (CTRCD) but is influenced by blood pressure changes. This limitation may be overcome by assessment of myocardial work (MW), which incorporates blood pressure into the calculation.ObjectivesThis work aims to determine whether myocardial work indices (MWIs) can help diagnose or prognosticate CTRCD.MethodsIn this prospective cohort study, 136 women undergoing anthracycline and trastuzumab treatment for HER2+ breast cancer, underwent serial echocardiograms and cardiac magnetic resonance pre- and post-anthracycline and every 3 months during trastuzumab. GLS, global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency were measured. CTRCD was defined with cardiac magnetic resonance. Generalized estimating equations quantified the association between changes in GLS and MWIs and CTRCD at the current (diagnosis) and subsequent visit (prognosis). Regression tree analysis was used to explore the combined use of GLS and MW for the diagnostic/prognostic assessment of CTRCD.ResultsBaseline left ventricular ejection fraction (LVEF) was 63.2 ± 4.0%. Thirty-seven (27.2%) patients developed CTRCD. An absolute change in GLS (standardized odds ratio [sOR]: 1.97 [95% CI: 1.07-3.66]; P = 0.031) and GWI (sOR: 1.73 [95% CI: 1.04-2.85]; P = 0.033) were associated with concurrent CTRCD. An absolute change in GLS (sOR: 1.79 [95% CI: 1.22-2.62]; P = 0.003), GWI (sOR: 1.67 [95% CI: 1.20-2.32]; P = 0.003), and GCW (sOR: 1.65 [95% CI: 1.17-2.34]; P = 0.005) were associated with subsequent CTRCD. Change in GWI and GCW demonstrated incremental value over GLS and clinical factors for the diagnosis of concurrent CTRCD. In a small group with a GLS change <3.3% (absolute), and a >21 mm Hg reduction in systolic blood pressure, worsening of GWI identified patients with higher probability of concurrent CTRCD (24.0% vs 5.2%). MWIs did not improve identification of subsequent CTRCD beyond knowledge of GLS change.ConclusionsGLS can be used to diagnose and prognosticate cardiac magnetic resonance (CMR) defined CTRCD, with additional value from MWIs in selected cases. (Evaluation of Myocardial Changes During Breast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI [EMBRACE-MRI]; NCT02306538)     

Left ventricular myocardial oxygen demand and subclinical dysfunction in patients with severe obesity referred for bariatric surgery

Background and aimsIncreased myocardial oxygen (O₂) demand carries higher cardiovascular risk in hypertension. We hypothesized that myocardial O₂ demand is increased in severe obesity and linked to early left ventricular (LV) dysfunction.Methods and resultsBaseline data from 106 severely obese subjects referred for gastric bypass surgery (42 ± 11 years, 74% women, body mass index [BMI] 41.9 ± 4.8 kg/m², 32% with hypertension) in the prospective FatWest (Bariatric Surgery on the West Coast of Norway) study was used. LV systolic function was assessed by biplane ejection fraction (EF), midwall shortening (MWS) and endocardial global longitudinal strain (GLS), and LV diastolic function by mitral annular early diastolic velocity (e’). Myocardial O₂ demand was estimated from the LV mass-wall stress-heart rate product (high if > 1.62 × 10⁶/2.29 × 10⁶ g kdyne/cm² bpm in women/men). High myocardial O₂ demand was found in 33% and associated with higher BMI and high prevalence of low GLS (65%) and low MWS (63%) despite normal EF. In ROC analyses, higher myocardial O₂ demand discriminated between patients with low vs. normal MWS and GLS (area under curve 0.71 and 0.63, p < 0.05). In successive multiple regression analyses, higher myocardial O₂ demand was associated with lower LV MWS, GLS and average e’, respectively, independent of age, gender, BMI, pulse pressure, diabetes mellitus, and EF (all p < 0.05).ConclusionIn obese patients without known heart disease and with normal EF referred for bariatric surgery, high myocardial O₂ demand is associated with lower myocardial function whether assessed by GLS or MWS independent of confounders.Clinicaltrials.gov identifierNCT01533142;     

Pulmonary Artery Strain Predicts Prognosis in Pulmonary Arterial Hypertension

BackgroundCurrent cardiac magnetic resonance (CMR) imaging in pulmonary arterial hypertension (PAH) focuses on measures of ventricular function and coupling.ObjectivesThe purpose of this study was to evaluate pulmonary artery (PA) global longitudinal strain (GLS) as a prognostic marker in patients with PAH.MethodsThe authors included 169 patients with PAH from the ASPIRE (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) and INITIATE (Integrated computatioNal modelIng of righT heart mechanIcs and blood flow dynAmics in congeniTal hEart disease) registries, and 82 normal controls with similar age and gender distributions. PA GLS was derived from CMR feature tracking. Right ventricular measurements including volumes, ejection fraction, and right ventricular GLS were also derived from CMR. Patients were followed up a median of 34 months with all-cause mortality as the primary endpoint. Other known risk scores were collected, including the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) 2.0 and COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) 2.0 scores.ResultsOf 169 patients (mean age: 57 ± 15 years; 80% female), 45 (26.6%) died (median follow-up: 34 months). Mean PA GLS was 23% ± 6% in normal controls and 10% ± 5% in patients with PAH (P < 0.0001). Patients with PA GLS <9% had a higher risk of mortality than those with PA GLS ≥9% (P < 0.001), and this was an independent predictor of mortality in PAH on multivariable analysis after adjustment for known risk factors (HR: 2.93; P = 0.010). Finally, in patients with PAH, PA GLS provided incremental prognostic value over the REVEAL 2.0 (global chi-square; P = 0.001; C statistic comparison; P = 0.030) and COMPERA 2.0 (global chi-square; P = 0.001; C statistic comparison; P = 0.048).ConclusionsPA GLS confers incremental prognostic utility over the established risk scores for identifying patients with PAH at higher risk of death, who may be targeted for closer monitoring and/or intensified therapy.     

Evolution of Myocardial Dysfunction in Asymptomatic Patients at Risk of Heart Failure

ObjectivesThe determinants of changes in systolic and diastolic parameters in patients age >65 years, at risk of heart failure (HF), and with and without asymptomatic type 2 diabetes mellitus (T2DM) was assessed by echocardiography. The association between metformin and myocardial function was also assessed.BackgroundThe increasing prevalence of T2DM will likely further fuel the epidemic of HF. Understanding the development or progression of left ventricular (LV) dysfunction may inform effective measures for HF prevention.MethodsA total of 982 patients with at least one HF risk factor (hypertension, obesity, or T2DM) were recruited from 2 community-based populations and divided into 2 groups: T2DM (n = 431, age 71 ± 4 years) and non-T2DM (n = 551, age 71 ± 5 years). Associations of metformin therapy were evaluated in the T2DM group. All underwent a comprehensive echocardiogram, including global longitudinal strain (GLS) and diastolic function (transmitral flow [E], annular velocity [e’]) at baseline and follow-up (median 19 months [interquartile range: 17 to 26 months]). Comparisons were facilitated by propensity matching.ResultsA reduction in GLS was observed in the T2DM group (baseline ?17.8 ± 2.6% vs. follow-up ?17.4 ± 2.8%; p = 0.003), but not in the non-T2DM group (?18.7 ± 2.7% vs. ?18.6 ± 3.0%; p = 0.41). Estimated LV filling pressures increased in both the T2DM group (p = 0.001) and the non-T2DM group (p = 0.04). Metformin-treated patients with T2DM did not increase estimated LV filling pressure (E/e’ baseline 8.9 ± 2.7 vs. follow-up 9.1 ± 2.7; p = 0.485) or change e’ (7.6 ± 1.5 cm/s vs. 7.6 ± 1.8 cm/s; p = 0.88). After propensity matching, metformin was associated with a smaller change in e’ (β = 0.58 [95% CI: 0.13 to 1.03]; p = 0.013) and E/e’ (β = ?0.96 [95% CI: ?1.66 to ?0.26]; p = 0.007) but was not associated with a change in GLS (p = 0.46).ConclusionsOver 2 years, there is a worsening of GLS and LV filling pressures in asymptomatic diabetic patients with HF risk factors. Metformin use is associated with less deterioration of LV filling pressures and myocardial relaxation but had no association with systolic function.     

Clinical Characteristics and Prognostic Importance of Left Ventricular Apical Aneurysms in Hypertrophic Cardiomyopathy

BackgroundLeft ventricular (LV) apical aneurysms in hypertrophic cardiomyopathy (HCM) are a recognized risk marker for adverse cardiovascular events. There is variable practice among clinicians and discordance between international guidelines regarding treatment recommendations and prognostication for this important phenotype.ObjectivesThe authors sought to describe the morphology, clinical course, and risk of adverse events in a large single-center cohort of HCM patients with LV apical aneurysms.MethodsThis study analyzed 160 HCM patients with an LV apical aneurysm who were evaluated in our dedicated HCM clinic between January 1997 and April 2021.ResultsMean age was 59.1 ± 13.6 years, and 71% of these patients were male. Mean aneurysm size was 1.77 ± 1.04 cm. Over 6.2 ± 4.8 years, 14 (9%) patients had a sudden cardiac death (SCD) event, including appropriate therapy from an implantable cardioverter-defibrillator (ICD) or resuscitation from cardiac arrest (annualized event rate 1.77%/y), 39 (24%) had either a thromboembolic stroke or apical thrombus formation (2.9%/y), and 14 (9%) developed LV systolic dysfunction with an ejection fraction (EF) <50% (1.28%/y). HRs for SCD, stroke or thrombus, and EF <50% per 1-cm increase in aneurysm size were 1.69 (P = 0.007), 1.60 (P = 0.0002), and 1.63 (P = 0.01), respectively. Aneurysm size ≥2 cm was associated with a 5-year SCD rate of 9.7%, compared with 2.9% for aneurysm size <2 cm (log-rank P = 0.037). This subgroup also had higher risk of stroke/thrombus formation (HR: 2.20; P = 0.002), with an annualized event rate of 2.7%/year. A total of 39 (24%) patients reached the combined end point of SCD, stroke, or LV dysfunction (2.12%/y) with an HR of 1.47/cm increase in aneurysm size (P = 0.003) and an HR of 2.22 for patients with aneurysm size ≥2 cm (P = 0.02).ConclusionsIncreasing aneurysm size confers poorer prognosis. Aneurysm size ≥2 cm should alert potential consideration for prophylactic anticoagulation and primary prevention ICDs.     

3-Dimensional Strain Analysis of Hypertrophic Cardiomyopathy: Insights From the NHLBI International HCM Registry

BackgroundAbnormal global longitudinal strain (GLS) has been independently associated with adverse cardiac outcomes in both obstructive and nonobstructive hypertrophic cardiomyopathy.ObjectivesThe goal of this study was to understand predictors of abnormal GLS from baseline data from the National Heart, Lung, and Blood Institute (NHLBI) Hypertrophic Cardiomyopathy Registry (HCMR).MethodsThe study evaluated comprehensive 3-dimensional left ventricular myocardial strain from cine cardiac magnetic resonance in 2,311 patients from HCMR using in-house validated feature-tracking software. These data were correlated with other imaging markers, serum biomarkers, and demographic variables.ResultsAbnormal median GLS (> –11.0%) was associated with higher left ventricular (LV) mass index (93.8 ± 29.2 g/m² vs 75.1 ± 19.7 g/m²; P < 0.0001) and maximal wall thickness (21.7 ± 5.2 mm vs 19.3 ± 4.1 mm; P < 0.0001), lower left (62% ± 9% vs 66% ± 7%; P < 0.0001) and right (68% ± 11% vs 69% ± 10%; P < 0.01) ventricular ejection fractions, lower left atrial emptying functions (P < 0.0001 for all), and higher presence and myocardial extent of late gadolinium enhancement (6 SD and visual quantification; P < 0.0001 for both). Elastic net regression showed that adjusted predictors of GLS included female sex, Black race, history of syncope, presence of systolic anterior motion of the mitral valve, reverse curvature and apical morphologies, LV ejection fraction, LV mass index, and both presence/extent of late gadolinium enhancement and baseline N-terminal pro–B-type natriuretic peptide and troponin levels.ConclusionsAbnormal strain in hypertrophic cardiomyopathy is associated with other imaging and serum biomarkers of increased risk. Further follow-up of the HCMR cohort is needed to understand the independent relationship between LV strain and adverse cardiac outcomes in hypertrophic cardiomyopathy.     

Additional Prognostic Value of 2D Right Ventricular Speckle-Tracking Strain for Prediction of Survival in Heart Failure and Reduced Ejection Fraction: A Comparative Study With Cardiac Magnetic Resonance

ObjectivesThis study sought to compare the prognostic value of 2-dimensional (2D) right ventricular (RV) speckle tracking (STE) against cardiac magnetic resonance (CMR) RV ejection fraction (EF) and feature tracking (FT) and conventional echocardiographic parameters on overall and cardiovascular (CV) survival in patients with heart failure with reduced EF (HFrEF).BackgroundPrior works showed that RV systolic function predicts prognosis in HFrEF. 2D RVSTE had recently been proposed as new echocardiographic method to evaluate RV dysfunction.MethodsA total of 266 patients with HFrEF (mean LVEF 23 ± 7%, 60 ± 14 years of age; 29% women) underwent RV function assessment using CMR and 2D echocardiography and were followed for a primary endpoint of overall death and secondary endpoint of CV death.ResultsAverage CMR-RVEF was 42 ± 15%, average STE RV global longitudinal strain (STE-RVGLS) was −18.0 ± 4.9%, and average CMR-FT-RVGLS was −11.8 ± 4.3%. After a median follow-up of 4.7 years, 102 patients died, 84 of a CV cause. RVEF, FT-RVGLS, tricuspid annulus plane systolic excursion (TAPSE), fractional area change (FAC), and STE-RVGLS were significant univariate predictors of overall and cardiac death. In multivariate Cox regression, age, ischemic etiology, diabetes, New York Heart Association functional class III to IV, and beta-blocker treatment were independent clinical predictors of overall mortality. CMR-RVEF (chi-square to enter = 3.9; p < 0.05), FT-RVGLS (chi-square to enter 3.7; p = 0.05), FAC (chi-square to enter 6.2; p = 0.02), and TAPSE (chi-square to enter = 4.1; p = 0.04) provided additional prognostic value over these baseline parameters, but the additional predictive value of STE-RVGLS (chi-square to enter = 10.8; p < 0.001) was significantly (p < 0.05) higher than the other tests. Additional hazard ratio to predict overall mortality was 2.5 (95% confidence interval [CI]: 1.6 to 3.9) for STE-RVGLS <−19%, 2.15 (95% CI: 1.34 to 3.43) for TAPSE >15 mm, 1.6 (95% CI: 1.02 to 2.49) for FAC >39%, 1.93 (95% CI: 1.25 to 2.99) for RVEF >41%, and 1.87 (95% CI: 1.10 to 3.19) for CMR-FT-RVGLS <−15%.Conclusions2D RVGLS provides strong additional prognostic value to predict overall and CV mortality in HFrEF, with higher predictive value than CMR-RVEF, CMR-FT-RVGLS, TAPSE, or FAC. This supports use of STE-RVGLS to identify higher-risk HFrEF patients.     

First-Phase Ejection Fraction Predicts Response to Cardiac Resynchronization Therapy and Adverse Outcomes

ObjectivesThe aim of this study was to examine the value of first-phase ejection fraction (EF1), to predict response to cardiac resynchronization therapy (CRT) and clinical outcomes after CRT.BackgroundCRT is an important treatment for patients with chronic heart failure. However, even in carefully selected cases, up to 40% of patients fail to respond. EF1, the ejection fraction up to the time of maximal ventricular contraction, is a novel sensitive echocardiographic measure of early systolic function and might relate to response to CRT.MethodsAn initial retrospective study was performed in 197 patients who underwent CRT between 2009 and 2018 and were followed to determine clinical outcomes at King’s Health Partners in London. A validation study (n = 100) was performed in patients undergoing CRT at Barts Heart Centre in London.ResultsVolumetric response rate (reduction in end-systolic volume ≥15%) was 92.3% and 12.1% for those with EF1 in the highest and lowest tertiles (P < 0.001). A cutoff value of 11.9% for EF1 had >85% sensitivity and specificity for prediction of response to CRT; on multivariate binary logistic regression analysis incorporating previously defined predictors, EF1 was the strongest predictor of response (odds ratio [OR]: 1.56 per 1% change in EF1; 95% CI: 1.37-1.78; P < 0.001). EF1 was also the strongest predictor of improvement in clinical composite score (OR: 1.11; 95% CI: 1.04-1.19; P = 0.001). Improvement in EF1 at 6 months after CRT implantation (6.5% ± 5.8% vs 1.8% ± 4.3% in responders vs nonresponders; P < 0.001) was the best predictor of heart failure rehospitalization and death after median follow-up period of 20.3 months (HR: 0.81; 95% CI: 0.73-0.90; P < 0.001). In the validation cohort, EF1 was a similarly 1strong predictor of response (OR: 1.45; 95% CI: 1.23-1.70; P < 0.001) as in the original cohort.ConclusionsEF1 is a promising marker to identify patients likely to respond to CRT.     

Diagnostic Accuracy of the 2016 Guideline-Based Echocardiographic Algorithm to Estimate Invasively-Measured Left Atrial Pressure by Direct Atrial Cannulation

BackgroundAlthough estimation of left ventricular filling pressure (LVFP) using an integrated echocardiographic algorithm is recommended, the usefulness of this algorithm has not been fully validated.ObjectivesThe purpose of this study was to investigate the reliability of an algorithmic classification system using invasively measured left atrial pressure (LAP) in a large-scale cohort.MethodsThe authors enrolled 1,967 patients (age 68 ± 10 years) whose LAP was directly measured within the left atrium during catheter ablation for atrial fibrillation. Patients were classified into 3 groups based on the echocardiographic algorithm: normal (group N, n = 1,282), undetermined (group U, n = 160), and elevated (group E, n = 346) LAP groups. Invasively measured LAP and echocardiographic parameters estimating LVFP were compared among the groups.ResultsThe median LAP was 12.6 ± 5.7 mm Hg in the entire cohort. LAP was significantly higher in group E than that in the other groups (groups E vs U vs N, 14.2 ± 6.3 mm Hg vs 13.5 ± 5.9 mm Hg vs 12.0 ± 5.5 mm Hg; P < 0.001). Among group E patients, 43.1% had elevated LAP (≥15 mm Hg), whereas 56.9% had normal LAP (<15 mm Hg). Of the patients in group N, 69.0% had normal LAP, whereas 31% had elevated LAP. Although the correlation between invasively measured LAP and E/e′, peak tricuspid regurgitant velocity, and left atrial volume index was modest, the number of abnormal values correlated significantly with elevated LAP (P < 0.001).ConclusionsThe classification using combined echocardiographic parameters in the recommendations may be useful for detecting patients with normal LVFP but may be limited for detecting elevated LVFP.     

Outcomes in Patients With Hypertrophic Cardiomyopathy and Left Ventricular Systolic Dysfunction

BackgroundEnd-stage (ES) hypertrophic cardiomyopathy (HCM) has been considered a particularly grim and unfavorable disease complication, associated with substantial morbidity and mortality, frequently requiring heart transplant. Previous reports have included small numbers of patients with relatively short follow-up, predominantly in prior treatment eras.ObjectivesThe purpose of this study was to re-evaluate clinical profile and prognosis for end-stage heart failure in a large HCM cohort with contemporary management strategies.MethodsPatients at Tufts HCM Institute, from 2004 to 2017, were identified with ES and systolic dysfunction (ejection fraction [EF] <50%), followed for 5.8 ± 4.7 years (up to 18 years).ResultsOf the 2,447 patients, 118 (4.8%) had ES-HCM (EF 39 ± 9%; range 12% to 49%) at age 48 ± 15 years. Notably, over follow-up, 57 patients (48%) achieved clinical stability in New York Heart Association functional classes I/II with medical treatment (or cardiac resynchronization therapy), including 6 patients ≥10 years from ES diagnosis (up to 14 years). In total, 61 other patients (52%) developed refractory heart failure to disabling New York Heart Association functional classes III/IV (5.2%/year); 67% have survived, including 31 with heart transplant. Of the 118 ES patients, 21 had appropriate implantable cardioverter-defibrillator (ICD) therapy terminating potentially lethal tachyarrhythmias, with no difference in frequency of events in patients with EF 35% to 49% versus EF <35% (17% vs. 19%; p = 0.80). With all available treatment modalities, ES-related mortality was 1.9%/year, with 10-year survival of 85% (95% confidence interval: 77% to 94%). Mortality was 4-fold lower than previously reported for ES (8.0%/year), but exceeded 10-fold HCM with preserved EF (0.2%/year; p < 0.001).ConclusionsAlthough ES remains an important complication of HCM, contemporary treatment strategies, including ICDs and heart transplant, are associated with significantly lower mortality than previously considered. Primary prevention ICDs should be considered when EF is <50% in HCM. Rapid heart failure progression is not an inevitable consequence of ES, and some patients experience extended periods of clinical stability.     

Propensity-Matched 1-Year Outcomes Following Transcatheter Aortic Valve Replacement in Low-Risk Bicuspid and Tricuspid Patients

ObjectivesThe aim of this study was to compare 1-year outcomes after transcatheter aortic valve replacement (TAVR) in low surgical risk patients with bicuspid aortic stenosis to patients with tricuspid aortic stenosis.BackgroundThe pivotal TAVR trials excluded patients with bicuspid aortic valves. The Low Risk Bicuspid Study 30-day primary endpoint of death or disabling stroke was 1.3%.MethodsThe Low Risk Bicuspid Study is a prospective, single-arm, TAVR trial that enrolled patients from 25 U.S. sites. A screening committee confirmed bicuspid anatomy and valve classification on computed tomography using the Sievers classification. Valve sizing was by annular measurements. An independent clinical events committee adjudicated all serious adverse events, and an independent core laboratory assessed all echocardiograms. The 150 patients from the Low Risk Bicuspid Study were propensity matched to the TAVR patients in the randomized Evolut Low Risk Trial using the 1:1 5- to-1-digit greedy method, resulting in 145 pairs.ResultsAll-cause mortality or disabling stroke at 1 year was 1.4% in the bicuspid and 2.8% in the tricuspid group (P = 0.413). A pacemaker was implanted in 16.6% of bicuspid and 17.9% of tricuspid patients (P = 0.741). The effective orifice area was similar between groups at 1 year (2.2 ± 0.7 cm² vs 2.3 ± 0.6 cm², P = 0.677) as was the mean gradient (8.7 ± 3.9 mm Hg vs 8.5 ± 3.1 mm Hg, P = 0.754). Fewer patients in the bicuspid group had mild or worse paravalvular leak (21.3% vs 42.6%, P < 0.001).ConclusionsThere were no significant differences in clinical or forward flow hemodynamic outcomes between the propensity-matched groups at 1 year.     

The Mitral Annular Disjunction of Mitral Valve Prolapse: Presentation and Outcome

ObjectivesThe aim of this study was to assess in patients with mitral valve prolapse (MVP) mitral annular disjunction (MAD) prevalence, phenotypic characteristics, and long-term outcomes (clinical arrhythmic events and excess mortality).BackgroundClinical knowledge regarding MAD of MVP remains limited and controversial, and its potential link with untoward outcomes is unsubstantiated.MethodsA cohort of 595 (278 women, mean age 61 ± 16 years) consecutive patients with isolated MVP, with comprehensive clinical, rhythmic, Doppler echocardiographic, and consistent MAD assessment, were examined. MAD prevalence, associated MVP phenotypes, and outcomes (survival, clinical arrhythmic events) starting at diagnostic echocardiography were analyzed. To balance important baseline differences, propensity scoring matching was conducted among patients with and those without MAD.ResultsThe presence of MAD was common (n = 186 [31%]) in patients with MVP, generally in younger patients, and was not random but was independently associated with severe myxomatous disease involving bileaflet MVP and marked leaflet redundancy (both P ≤ 0.0002). The presence of MAD was also independently associated with a larger left ventricle (P = 0.005). Age-matched cohort survival after MVP diagnosis was not worse with MAD (10-year survival 93% ± 2% for patients without MAD and 97% ± 1% for those with MAD; P = 0.40), even adjusted comprehensively for MVP characteristics (P = 0.80) and accounting for time-dependent mitral surgery (P = 0.60). During follow-up, 170 patients had clinical arrhythmic events (ventricular tachycardia, n = 159; arrhythmia ablation, n = 14; cardioverter-defibrillator implantation, n = 14; sudden cardiac death, n = 3). MAD was independently associated with higher risk for arrhythmic events (adjusted HR: 2.60; 95% CI: 1.87-3.62; P < 0.0001). The link between MAD and arrhythmic events persisted with time-dependent mitral surgery (adjusted HR: 2.54; 95% CI: 1.84-3.50; P < 0.0001), was strong under medical management (adjusted HR: 3.21; 95% CI: 2.03-5.06; P < 0.0001) but was weaker after mitral surgery (adjusted HR: 2.07; 95% CI: 1.24-3.43; P = 0.005).ConclusionsThis large cohort with MVP comprehensively characterized shows that MAD is frequent at MVP diagnosis and is strongly linked to advanced myxomatous degeneration. The presence of MAD was independently associated with long-term excess incidence of clinical arrhythmic events. However, within the first 10 years post-diagnosis, MAD was not linked to excess mortality, and although reassurance should be provided from the survival point of view, careful monitoring for arrhythmias is in order for MAD.     

Sex Differences in LV Remodeling and Hemodynamics in Aortic Stenosis: Sex-Specific Criteria for Severe Stenosis?

BackgroundThe current criteria for aortic stenosis (AS) severity have not incorporated sex-related differences.ObjectivesThe authors investigated sex-related serial changes in left ventricular (LV) structure/function and hemodynamics in AS.MethodsSerial echocardiograms of patients with severe AS (time 0; aortic valve area [AVA] ≤1 cm²) and ≥1 previous echocardiogram were compared between sexes.ResultsOf 927 patients (time 0: AVA 0.87 ± 0.11 cm², peak velocity 4.03 ± 0.65 m/s, mean Doppler systolic pressure gradient [MG] 40.6 ± 13.1 mm Hg), 393 (42%) were women. Women had smaller body surface area (BSA) (1.77 ± 0.22 m² vs 2.03 ± 0.20 m²; P < 0.001), lower stroke volume (SV) (81.1 ± 17.2 mL vs 88.3 ± 18.6 mL; P < 0.001), and more frequent low-gradient severe AS (n = 196 [50%] vs n = 181 [34%]; P < 0.001). Women consistently had smaller AVA, indexed AVA (AVAi), peak velocity, and MG than men. The difference in aortic valve gradient lessened when AVAi ≤0.6 cm²/m² was applied as severe AS (n = 694, women 43%, AVA 0.95 ± 0.17 cm², AVAi 0.50 ± 0.07 cm²/m²). Peak velocity (3.83 ± 0.66 m/s) and MG (36.5 ± 13.2 mm Hg) were lower based on AVAi severity criteria compared to those based on AVA. Men had a lower left ventricular ejection fraction (LVEF) (55.8% ± 14.8% vs 61.1% ± 11.7%; P < 0.001) and greater reduction in SV (?13.3 ± 19.6 mL vs ?7.4 ± 16.4 mL; P < 0.001) as AS progressed from moderate to severe. Concentric LV hypertrophy was more common and E/e? higher in women (21.2 ± 10.9 vs 18.8 ± 9.1; P < 0.001). SV, LVEF, AVA, peak velocity, and MG became precipitously worse when AVA reached 1.2 cm² in both sexes.ConclusionsSmaller BSA in women yields lower SV, resulting in lower aortic valve gradient than men. Indexed parameters by BSA are thus important in sex-related differences of aortic valve hemodynamics, but AVAi ≤0.6 cm²/m² includes individuals with moderate AS. Elevated filling pressure is more common in women. Men experience a larger reduction in SV and LVEF as AS progresses. The definition of AS severity may require different criteria between sexes.