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.

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.

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.

A multi-modal diagnostic model improves detection of cardiac amyloidosis among patients with diagnostic confirmation by cardiac biopsy.

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 (<0.5 mV) showed good discrimination for cardiac amyloidosis with an optimism-corrected c-index of 0.87 (95% CI 0.83-0.92). The diagnostic accuracy of this model (79% sensitivity, 84% specificity) surpassed that of traditional screening parameters, such as IWT in the absence of left ventricular hypertrophy on ECG (98% sensitivity, 20% specificity) and IWT with low limb lead voltage (49% sensitivity, 91% specificity). 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.

BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension.

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-2α-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.

Interaction of Left Ventricular Remodeling and Regional Dyssynchrony on Long-Term Prognosis after Cardiac Resynchronization Therapy.

BACKGROUND: Left ventricular (LV) remodeling in heart failure (HF) manifested by chamber dilatation is associated with worse clinical outcomes. However, the impact of LV dilatation on the association of measures of dyssynchrony with long-term prognosis and resynchronization potential after cardiac resynchronization therapy (CRT) remains unclear. METHODS: Two hundred sixty CRT patients in New York Heart Association classes II to IV, with ejection fractions ≤ 35% and QRS intervals ≥ 120 msec, were prospectively studied. Quantitative echocardiographic assessment of LV volumes and mechanical dyssynchrony by radial strain was conducted at both baseline and 6-month follow-up. Primary outcome events were predefined as death or HF hospitalization, and secondary outcome events were defined as all-cause death over the 4 years after CRT. RESULTS: Patients were divided into two groups using the median of the baseline indexed LV end-diastolic volume (EDVI). Patients with less dilated left ventricles (EDVI < 90 mL/m2) had improved prognosis compared to those with severely dilated left ventricles (EDVI ≥ 90 mL/m2) for both primary (adjusted hazard ratio [HR], 2.20; 95% CI, 1.44-3.38; P < .01) and secondary (adjusted HR, 1.94; 95% CI, 1.21-3.11; P < .01) events. Similarly, reduction in baseline dyssynchrony was associated with good prognosis for both the primary (HR, 0.39; 95% CI, 0.23-0.68; P = .001) and secondary (HR, 0.41; 95% CI, 0.22-0.75; P = .004) events. A linear association was found between each 10% reduction in dyssynchrony and events (P < .01). Notably, patients with less dilated left ventricles had nearly fourfold more frequent improvement in dyssynchrony compared to those with severely dilated left ventricles (odds ratio, 4.10; 95% CI, 1.81-9.28; P < .01). No other baseline prognostic marker was associated with the resynchronization ability of CRT. CONCLUSIONS: Patients with severe LV remodeling (EDVI ≥ 90 mL/m2) have a poor prognosis following CRT device implantation. This is most likely due to impaired resynchronization efficacy.

Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study.

OBJECTIVES: This study explored the association of vascular hormones with myocardial recovery and clinical outcomes in peripartum cardiomyopathy (PPCM). BACKGROUND: PPCM is an uncommon disorder with unknown etiology. Angiogenic imbalance may contribute to its pathophysiology. METHODS: In 98 women with newly diagnosed PPCM enrolled in the Investigation in Pregnancy Associated Cardiomyopathy study, serum was obtained at baseline for analysis of relaxin-2, prolactin, soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF). Left ventricular ejection fraction (LVEF) was assessed by echocardiography at baseline and 2, 6, and 12 months. RESULTS: Mean age was 30 ± 6 years, with a baseline of LVEF 0.35 ± 0.09. Relaxin-2, prolactin, and sFlt1 were elevated in women presenting early post-partum, but decreased rapidly and were correlated inversely with time from delivery to presentation. In tertile analysis, higher relaxin-2 was associated with smaller left ventricular systolic diameter (p = 0.006) and higher LVEF at 2 months (p = 0.01). This was particularly evident in women presenting soon after delivery (p = 0.02). No relationship was evident for myocardial recovery and prolactin, sFlt1 or VEGF levels. sFlt1 levels were higher in women with higher New York Heart Association functional class (p = 0.01) and adverse clinical events (p = 0.004). CONCLUSIONS: In women with newly diagnosed PPCM, higher relaxin-2 levels soon after delivery were associated with myocardial recovery at 2 months. In contrast, higher sFlt1 levels correlated with more severe symptoms and major adverse clinical events. Vascular mediators may contribute to the development of PPCM and influence subsequent myocardial recovery. (Investigation in Pregnancy Associate Cardiomyopathy [IPAC]; NCT01085955).

The prognostic significance of troponin I elevation in acute ischemic stroke.

BACKGROUND: The significance of cardiac troponin I (TnI) levels in patients with acute ischemic stroke remains unclear. METHODS: Data were prospectively collected on 1718 patients with acute ischemic stroke (2009-2010). Patients with positive TnI (peak TnI ≥0.1 µg/L) were assigned to the myocardial infarction (MI) group if they met diagnostic criteria. The remaining patients with positive TnI were assigned to the no-MI group. Patients were followed up for 1.4 ± 1.1 years. Primary outcome was inhospital and long-term all-cause mortality. RESULTS: Positive TnI was present in 309 patients (18%), 119 of whom (39%) were classified as having MI. Positive TnI was independently associated with older age, hypertension, smoking, peripheral arterial disease, heart failure, higher systolic blood pressure, higher serum creatinine, and lower heart rate (P < .01). Patients with MI had the highest inpatient mortality (P < .001) and the lowest survival rate by Kaplan-Meier analysis (P < .0001). Peak TnI greater than or equal to 0.5 µg/L, particularly if satisfying criteria for MI, was independently associated with long-term mortality (P < .0001); peak TnI less than 0.5 µg/L alone was not when adjusted for covariates. CONCLUSION: Positive TnI greater than or equal to 0.5 µg/L in patients with acute ischemic stroke was independently associated with worse outcomes. Patients with diagnosis of MI represent a particularly high-risk subgroup.

Echocardiographic strain and mortality in Black Americans with end-stage renal disease on hemodialysis.

End-stage renal disease (ESRD) presents a significant health burden and is associated with high cardiovascular morbidity and mortality. This is particularly true in African Americans who generally have higher rates of cardiovascular mortality. Outcomes in ESRD are related to extent of cardiovascular disease, but markers for outcome are not clearly established. Global longitudinal strain (GLS) has emerged as an important measure of left ventricular systolic function that is additive to traditional ejection fraction (EF). It can be measured on routine digital echocardiography and is reproducible. This study tested the hypothesis that GLS is associated with mortality in black Americans with ESRD and preserved EF. Forty-eight outpatients undergoing hemodialysis, 59.4 ± 13.3 years, with EF ≥50% were prospectively enrolled. GLS, measured by an offline speckle tracking algorithm, ranged from -8.6% to -22.0% with a mean of -13.4%, substantially below normal (-16% or more negative). The prevalence of left ventricular systolic dysfunction, as determined by GLS, was 89%. Patients were followed for an average of 1.9 years; all-cause mortality was 19% (9 deaths). GLS was significantly associated with mortality (hazard ratio 1.15, 95% confidence interval 1.02 to 1.30, p = 0.02), whereas EF was not. After adjustment for multiple potential confounders (age, gender, race, smoking, hypertension, diabetes, hyperlipidemia, coronary disease, heart failure, and EF), GLS remained strongly associated with mortality (hazard ratio 1.30, 95% confidence interval 1.10 to 1.56, p = 0.002). In conclusion, GLS is an important index in patients with ESRD, which is additive to EF as a marker for mortality in this high-risk group.

Characterization of right ventricular remodeling in pulmonary hypertension associated with patient outcomes by 3-dimensional wall motion tracking echocardiography.

BACKGROUND: Adverse right ventricular (RV) remodeling has significant prognostic and therapeutic implications to patients with pulmonary hypertension (PH). However, differentiating RV adaption from adverse remodeling associated with poor outcomes is difficult. We hypothesized that novel 3-dimensional (3D) wall motion tracking echocardiography can differentiate morphological features of RV adaption from adverse remodeling heralding an unfavorable short-term prognosis in patients with PH. METHODS AND RESULTS: We studied 112 subjects: 92 patients with PH and 20 normal controls with 3D wall motion tracking for RV end-systolic volume index (ESVi), RV ejection fraction (EF), and RV global area strain. Patients with PH also had invasive hemodynamic measurements. Pressure-volume relations classified patients with PH into 3 groups, such as RV adapted, RV adapted-remodeled, and RV adverse-remodeled. The predefined combined end point was PH-related hospitalization, death, or lung surgery (lung transplantation or pulmonary endarterectomy) during 6 months. The 92 patients with PH had significantly larger RV volumes, lower RVEF and global area strain than normal controls as expected. Patients with PH classified as RV adapted (ESVi, ≤72 mL/m(2)) had a more favorable clinical outcome than those classified as RV adapted-remodeled (ESVi, 73-113 mL/m(2)) or RV adverse-remodeled (ESVi, ≥114 mL/m(2)): hazard ratio, 0.15; 95% confidence intervals, 0.07 to 0.39; P<0.0001. RV adverse-remodeled patients (ESVi, ≥114 mL/m(2)) had worse short-term outcome than the RV adapted-remodeled patients: hazard ratio, 2.2; 95% confidence interval, 0.91 to 5.39; P=0.04. CONCLUSIONS: Quantitative 3D echocardiography in patients with PH demonstrated morphological subsets of RV adaption and remodeling associated with clinical outcomes.

Right ventricular apical pacing-induced left ventricular dyssynchrony is associated with a subsequent decline in ejection fraction.

BACKGROUND: In patients with normal left ventricular (LV) ejection fraction (EF), the interposition of chronic, high-dose right ventricular apical (RVA) pacing may produce late EF decline. OBJECTIVE: To test the hypothesis that LV dyssynchrony, defined echocardiographically and apparent early after interposition of pacing, would be greater in patients who subsequently demonstrated EF decline. METHODS: Ninety-one patients with normal prepacing EF who underwent atrioventricular node ablation and subsequent high-dose RVA pacing were studied. Transthoracic echocardiograms were performed early (median 4 months) and late (median 28 months) after interposition of pacing, with a significant decline in EF between these studies defined as ≥5%. Speckle-tracking longitudinal strain analysis of the early echocardiogram was performed to quantify dyssynchrony. In addition to standard dyssynchrony indices, a novel index of apex-to-base mechanical propagation delay (MPD) was used. RESULTS: Multivariable analysis determined that MPD of the septum correlated with a significant decline in EF, independent of all other dyssynchrony, clinical, or pacing variables. A septal MPD value exceeding 50 ms was associated with EF decline at 81% sensitivity and 88% specificity. CONCLUSIONS: Dyssynchrony, in particular septal MPD, measured early after interposition of high-dose RVA pacing predicted a significant late decline in EF in patients who had normal prepacing EF.

Usefulness of echocardiographically guided left ventricular lead placement for cardiac resynchronization therapy in patients with intermediate QRS width and non-left bundle branch block morphology.

The current guidelines most strongly support cardiac resynchronization therapy (CRT) for patients with heart failure with a QRS width of ≥150 ms and left bundle branch block (LBBB). Our objective was to assess the potential benefit of echocardiographically guided left ventricular (LV) lead positioning for patients with a QRS width <150 ms or non-LBBB as a substudy of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) prospective, randomized controlled trial. The STARTER trial randomized 187 patients with heart failure, a QRS of ≥120 ms, and ejection fraction of ≤35% to LV lead guided to the site of latest mechanical activation by speckle tracking radial strain versus routine implantation. The predefined primary end point was heart failure hospitalization or death within 2 years. This substudy included 151 CRT patients with matching echocardiographic and LV lead position data and complete follow-up data. Patients with a QRS width of 120 to 149 ms or non-LBBB and LV lead concordant or adjacent to the site of latest mechanical activation had favorable outcomes after CRT similar to those with LBBB or a QRS width of ≥150 ms. In contrast, patients with a QRS of 120 to 149 ms or non-LBBB and remote LV leads had unfavorable outcomes (hazard ratio 5.45, 95% confidence interval 2.36 to 12.6, p <0.001, and hazard ratio 4.92, 95% confidence interval 2.12 to 11.39, p <0.001, respectively, with significant interaction after adjusting for baseline variables, p = 0.038 and p = 0.008). In conclusion, LV lead positioning with respect to the echocardiographic site of latest activation was significantly associated with more favorable clinical outcomes in patients with a QRS duration <150 ms and/or non-LBBB. Additional prospective study is warranted.

Echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy: results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region trial.

BACKGROUND: Cardiac resynchronization therapy improves mortality and morbidity in patients with heart failure (HF) with wide QRS complex and diminished left ventricular (LV) function, but response is variable. METHODS AND RESULTS: The Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) was a prospective, double-blind, randomized controlled trial testing the hypothesis that an incremental benefit to cardiac resynchronization therapy would be gained by echo-guided (EG) transvenous LV lead placement versus a routine fluoroscopic approach. EG LV lead placement was attempted at the site of latest time to peak radial strain by speckle tracking echocardiography. The prespecified primary end point was first HF hospitalization or death. Of 187 New York Heart Association class II to IV patients with HF (62% ischemic; ejection fraction 26±6%; QRS 159±27 ms), 110 were randomized to EG and 77 to routine strategies. Primary events included 30 deaths and 37 HF hospitalizations over 1.8 years. Using intention-to-treat, patients randomized to an EG strategy had a significantly more favorable event-free survival (hazard ratio, 0.48; 95% confidence interval, 0.28-0.82; P=0.006). Exact or adjacent concordance of LV lead with latest site could be achieved in 85% of the EG group and occurred fortuitously in 66% of controls (P=0.010) and was associated with an improvement in event-free survival (hazard ratio, 0.40; 95% confidence interval, 0.22-0.71; P=0.002). CONCLUSIONS: A strategy of EG LV lead placement for cardiac resynchronization therapy improved patient outcomes by reducing the combined risk of death or HF hospitalizations and has implications for delivery of cardiac resynchronization therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00156390.

Prediction of response to cardiac resynchronization therapy by speckle tracking echocardiography using different software approaches.

BACKGROUND: Although several echocardiographic approaches exist to quantify mechanical dyssynchrony, the comparative ability of different manufacturers' speckle-tracking software programs to predict response to cardiac resynchronization therapy (CRT) is unknown. METHODS: Eighty-four patients with heart failure referred for CRT were studied (mean age, 64 +/- 12 years; mean ejection fraction [EF], 26 +/- 7%; mean QRS duration, 157 +/- 26 ms). Dyssynchrony was assessed using the same midventricular short-axis digital cine loop for each patient with 3 different offline speckle-tracking strain analysis programs: software A, speckle-tracking two-dimensional strain; software B, velocity vector imaging strain; and software C, speckle-tracking strain. Significant dyssynchrony was defined as an anterior septum-to-posterior wall delay > or =130 ms. Follow-up was available for 57 patients (mean, 7 +/- 4 months). Response to CRT was defined as an EF increase > or =15%. RESULTS: Variability between software results was observed when patients had large degrees of dyssynchrony (> or =200 ms), with limits of agreement from 123 to 214 ms. However, close agreement for identifying patients with significant dyssynchrony was observed: 91% for software A versus B, 96% for software A versus C, and 93% for software B versus C. Importantly, the 3 software approaches' ability to predict EF outcome had similar sensitivities, specificities, and areas under receiver operating characteristic curves: 0.87, 0.86, and 0.86, respectively. CONCLUSIONS: Radial strain dyssynchrony analyses by 3 different speckle-tracking software programs were similarly able to predict EF response to CRT. Although variability in absolute values of dyssynchrony was observed, there was close agreement for determining the presence or absence of significant dyssynchrony. Speckle-tracking echocardiography has potential as a means to quantify dyssynchrony in a multicenter clinical trial or clinical practice.

Echocardiographic speckle tracking radial strain imaging to assess ventricular dyssynchrony in a pacing model of resynchronization therapy.

BACKGROUND: Speckle tracking imaging is a promising new echocardiographic method to assess left ventricular (LV) mechanical dyssynchrony. Our aim was to assess a new speckle tracking regional strain algorithm by comparison with angle-corrected tissue Doppler (TD) in an animal model of left bundle branch block and cardiac resynchronization therapy. METHODS AND RESULTS: Ten open-chest dogs had routine gray-scale and TD images of the mid-LV short-axis plane. Electrical activation was altered by pacing from right ventricular, LV free wall, and biventricular sites to create various degrees of mechanical dyssynchrony and alter regional function. Segmental time to peak strain, peak strain, and frame-by-frame strain were measured by angle-corrected TD, TD M-mode, and speckle tracking on the same digital cineloop. Of 240 possible paired TD and speckle tracking segments, data were available for 222 segments (93%); images with catheter artifacts were prospectively excluded. Comparative overall time to peak strain by each method correlated well: r = 0.96, bias = -6 +/- 20 ms. Of 80 possible paired M-mode TD and speckle tracking segments, strain data were available for 76 segments (95%). Comparative overall time to peak strain, peak strain, and frame-by-frame strain analysis in 1012 frames by each method correlated well: r = 0.98, bias of 1 +/- 14 ms; r = 0.82, bias of 3% +/- 7%; and r = 0.91, bias of 0% +/- 6%, respectively. CONCLUSION: Regional strain analysis using echocardiographic speckle tracking radial strain strongly correlated with strain by angle-corrected TD imaging in an animal model of dyssynchrony. Speckle tracking radial strain has potential for clinical applications.

The role of tissue Doppler and strain imaging in predicting response to CRT.

AIMS: Several echocardiographic methods have been proposed to assist in patient selection for cardiac resynchronization therapy (CRT). The prevailing hypothesis is that echocardiography may be superior to the electrocardiogram to qualify abnormalities in regional mechanical activation, because QRS widening is only a surrogate for ventricular dyssynchrony. METHODS AND RESULTS: This review will focus on tissue Doppler (TD) and strain imaging, including their advantages and disadvantages for patient selection for CRT. Colour-coded TD remains to be one of the most promising means to quantify dyssynchrony. Tissue Doppler velocity data have a more favourable signal-to-noise ratio compared with TD strain or strain rate imaging. However, velocity data are affected by Doppler angle of incidence and passive or tethering motion. A newer promising method is speckle-tracking echocardiography to calculate strain. An opposing wall delay in peak TD velocity > or =65 ms has been associated with clinical and ventricular response to CRT. The initial experience with speckle tracking used the short-axis view to calculate radial strain. An anterior-septal to posterior wall peak strain delay > or =130 ms has been associated with an ejection fraction response to CRT. CONCLUSION: Although no ideal echo-Doppler method has yet been discovered to select patients for CRT, technical refinements and advances in understanding of pathophysiology continue to favourably impact on potential clinical applications.

Utility of hand-carried ultrasound for consultative cardiology.

Although the stethoscope has been an important part of the bedside cardiac diagnostic examination for generations of physicians, this clinical tool has been relatively unchanged in over 150 years. Echocardiography is established as an essential diagnostic imaging method for patients with known or suspected cardiovascular diseases. However, routine echocardiography systems are large and heavy, and although they are portable, they remain inconvenient for bedside patient rounds. Technologic advances have resulted in miniaturization of electronic components and small, lightweight ultrasound systems have been recently introduced. These hand-carried units offer clinically acceptable two-dimensional image quality for rapid "quick-look" bedside diagnostics, in particular focusing on global and regional left ventricular function and presence or absence of pericardial effusion. This article proposes a general approach to the rapid hand-carried ultrasound cardiac exam as an extension of the physical examination. It details case examples and reviews the initial clinical experience of hand-carried ultrasound on cardiac consultation rounds. Hand-carried ultrasound has promise to have an immediate impact on bedside patient management though expediting and facilitating the delivery of medical care.