Akiko Goda

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/m2) had a more favorable clinical outcome than those classified as RV adapted–remodeled (ESVi, 73–113 mL/m2) or RV adverse–remodeled (ESVi, ≥114 mL/m2): hazard ratio, 0.15; 95% confidence intervals, 0.07 to 0.39; P<0.0001. RV adverse–remodeled patients (ESVi, ≥114 mL/m2) 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.

Additive Prognostic Value of Echocardiographic Global Longitudinal and Global Circumferential Strain to Electrocardiographic Criteria in Patients With Heart Failure Undergoing Cardiac Resynchronization Therapy

Background—Response to cardiac resynchronization therapy is most favorable in patients with heart failure with QRS duration ≥150 ms and left bundle branch block and less predictable in those with QRS width 120 to 149 ms or non–left bundle branch block. Methods and Results—We studied 205 patients with heart failure referred for cardiac resynchronization therapy with QRS ≥120 ms and ejection fraction ⩽35%. We tested the hypothesis that contractile function using speckle-tracking echocardiographic global circumferential strain (GCS) from 2 short-axis views and global longitudinal strain (GLS) from 3 apical views add prognostic value to electrocardiographic criteria. There were 112 patients (55%) with GLS >−9% and 136 patients (66%) with GCS >−9%. During 4 years, 81 patients reached the combined primary end point (death, circulatory support, or transplant) and 120 reached the secondary end point (heart failure hospitalization or death). Both GLS >−9% and GCS >−9% were associated with increased risk of unfavorable events as follows: for the primary end point (hazard ratio=2.91; 95% confidence interval, 1.88–4.49; P<0.001) and (hazard ratio=3.73; 95% confidence interval, 2.39–5.82; P<0.001) for the secondary end point (hazard ratio=2.10; 95% confidence interval, 1.45–3.05; P<0.001) and (hazard ratio=3.25; 95% confidence interval, 2.23–4.75; P<0.001). In a prespecified subgroup of 120 patients with QRS 120 to 149 ms or non–left bundle branch block, significant associations of baseline GLS and GCS and outcomes remained: P=0.014 and P=0.002 for the primary end point and P=0.049 and P=0.001 for the secondary end point. Global strain measures had additive prognostic value to routine clinical or electrocardiographic parameters (P<0.001). Conclusions—Baseline GCS and GLS were significantly associated with long-term outcome after cardiac resynchronization therapy and had additive prognostic value to routine clinical and electrocardiographic selection criteria for cardiac resynchronization therapy.

Comparative long-term outcomes after cardiac resynchronization therapy in right ventricular paced patients versus native wide left bundle branch block patients

BACKGROUND The current guidelines do not clearly state when we should upgrade a patient with right ventricular pacing (RVP) to cardiac resynchronization therapy (CRT), although the deleterious effect of chronic RVP has been established with recent trials. OBJECTIVES The aims of this study were to compare the long-term survival after CRT in patients upgraded from RVP with that in patients with left bundle branch block (LBBB) with QRS duration ≥ 150 ms and to compare the mechanical properties associated with CRT response in these groups. METHODS Overall, 135 patients with implanted CRT from a single center (85 (63%) with native wide LBBB and 50 (37%) with RVP) were studied prospectively. Baseline left ventricular typical contraction pattern was determined using speckle tracking echocardiography in the apical 4-chamber view. The predefined end point was death, heart transplantation, or left ventricular assist device implantation over a period of 4 years. RESULTS Patients with RVP had a significantly favorable long-term outcomes with adjusted hazard ratio of 0.36 (95% confidence interval 0.14-0.96; P = .04). Both groups had ~70% of patients with typical contraction pattern. The absence of typical contraction pattern was associated with a higher risk of an end point with adjusted hazard ratio of 5.43 (95% confidence interval 2.31-12.72; P < .001). In patients with typical contraction pattern, activation of the apical septal segment occurred more frequently in the RVP group and of the base or mid septal segments in the LBBB group. CONCLUSION Patients with HF upgraded from RVP have more favorable long-term outcomes after CRT than do native LBBB patients with QRS duration ≥ 150 ms. Contraction pattern assessment can be used to identify potential responders in the RVP group.

Mechanical Dyssynchrony by Tissue Doppler Cross-Correlation is Associated with Risk for Complex Ventricular Arrhythmias after Cardiac Resynchronization Therapy.

BACKGROUND Tissue Doppler cross-correlation analysis has been shown to be associated with long-term survival after cardiac resynchronization defibrillator therapy (CRT-D). Its association with ventricular arrhythmia (VA) is unknown. METHODS From two centers 151 CRT-D patients (New York Heart Association functional classes II-IV, ejection fraction ≤ 35%, and QRS duration ≥ 120 msec) were prospectively included. Tissue Doppler cross-correlation analysis of myocardial acceleration curves from the basal segments in the apical views both at baseline and 6 months after CRT-D implantation was performed. Patients were divided into four subgroups on the basis of dyssynchrony at baseline and follow-up after CRT-D. Outcome events were predefined as appropriate antitachycardia pacing, shock, or death over 2 years. RESULTS Mechanical dyssynchrony was present in 97 patients (64%) at baseline. At follow-up, 42 of these 97 patients (43%) had persistent dyssynchrony. Furthermore, among 54 patients with no dyssynchrony at baseline, 15 (28%) had onset of new dyssynchrony after CRT-D. In comparison with the group with reduced dyssynchrony, patients with persistent dyssynchrony after CRT-D were associated with a substantially increased risk for VA (hazard ratio [HR], 4.4; 95% CI, 1.2-16.3; P = .03) and VA or death (HR, 4.0; 95% CI, 1.7-9.6; P = .002) after adjusting for other covariates. Similarly, patients with new dyssynchrony had increased risk for VA (HR, 10.6; 95% CI, 2.8-40.4; P = .001) and VA or death (HR, 5.0; 95% CI, 1.8-13.5; P = .002). CONCLUSIONS Persistent and new mechanical dyssynchrony after CRT-D was associated with subsequent complex VA. Dyssynchrony after CRT-D is a marker of poor prognosis.

Pharmacological Inhibition of mTOR Kinase Reverses Right Ventricle Remodeling and Improves Right Ventricle Structure and Function in Rats

Abstract Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, increased pulmonary artery (PA) pressure, right‐heart afterload and death. Mechanistic target of rapamycin (mTOR) promotes smooth muscle cell proliferation, survival, and pulmonary vascular remodeling via two functionally distinct mTOR complexes (mTORCs)‐1 (supports cell growth) and ‐2 (promotes cell survival), and dual mTORC1/mTORC2 inhibition selectively induces pulmonary arterial hypertension PA vascular smooth muscle cell apoptosis and reverses pulmonary vascular remodeling. The consequences of mTOR inhibition on right ventricle (RV) morphology and function are not known. Using SU5416/hypoxia rat model of pulmonary hypertension (PH), we report that, in contrast to activation of both mTORC1 and mTORC2 pathways in small remodeled PAs, RV tissues had predominant up‐regulation of mTORC1 signaling accompanied by cardiomyocyte and RV hypertrophy, increased RV wall thickness, RV/left ventricle end‐diastolic area ratio, RV contractility and afterload (arterial elastance), and shorter RV acceleration time compared with controls. Treatment with mTOR kinase inhibitor, PP242, at Weeks 6‐8 after PH induction suppressed both mTORC1 and mTORC2 in small PAs, but only mTORC1 signaling in RV, preserving basal mTORC2‐Akt levels. Vehicle‐treated rats showed further PH and RV worsening and profound RV fibrosis. PP242 reversed pulmonary vascular remodeling and prevented neointimal occlusion of small PAs, significantly reduced PA pressure and pulmonary vascular resistance, reversed cardiomyocyte hypertrophy and RV remodeling, improved max RV contractility, arterial elastance, and RV acceleration time, and prevented development of RV fibrosis. Collectively, these data show a predominant role of mTORC1 versus mTORC2 in RV pathology, and suggest potential attractiveness of mTOR inhibition to simultaneously target pulmonary vascular remodeling and RV dysfunction in established PH.

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. HighlightsReduction in baseline mechanical dyssynchrony after CRT in patients with HF is associated with significant reduction in mortality and HF hospitalization.Patients with extensive remodeling has poor prognosis after CRT because of a lack of mechanical resynchronization after CRT.There is a linear association between the amount of reduction in mechanical dyssynchrony after CRT device implantation and survival. Devising a strategy to follow patients treated with CRT devices by the assessment of dyssynchrony could be beneficial.

CORRELATION OF A NEW ECHOCARDIOGRAPHIC INDEX OF RIGHT VENTRICULAR REMODELING IN PULMONARY HYPERTENSION WITH INVASIVE HEMODYNAMICS IN RAT MODEL

Right ventricular (RV) remodeling is important to humans with pulmonary hypertension (PH). Small animal models of PH are used to investigate novel therapies, but assessment of RV remodeling is difficult. The aim was to compare a new RV remodeling index (echo RV to LV area ratio) to invasive

AN ECHOCARDIOGRAPHIC RISK SCORE FOR PREDICTION OF MORTALITY IN PATIENTS WITH PULMONARY HYPERTENSION

Pulmonary hypertension (PH) is a progressive disease with variable prognosis and expanding treatment options. Guidelines have supported individual echocardiographic prognostic markers, but their ability to predict mortality remain unclear. The aim was to assess the prognostic significance of

BIVENTRICULAR REMODELING BY THREE DIMENSIONAL ECHOCARDIOGRAPHY IS ASSOCIATED WITH OUTCOME IN PATIENTS WITH PULMONARY HYPERTENSION

Right ventricular (RV) remodeling is an important factor associated with outcome in patients with pulmonary hypertension (PH). However, the influence of RV remodeling on left ventricular (LV) morphology in PH and its association with outcomes are unclear. We studied 83 PH patients with 3-