Reverse Remodeling Effects of Sacubitril-Valsartan: Structural and Functional Optimization in Stage C Heart Failure.

Sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor, reduces all-cause mortality and the rate of heart failure hospitalizations in patients with heart failure with reduced ejection fraction. This study aimed to elucidate the benefits of initiating sacubitril-valsartan on ventricular remodeling in patients previously optimized on guideline-directed medical therapy. In this prospective, single-arm longitudinal study, 40 patients with heart failure with reduced ejection fraction who were optimized on guideline-directed medical therapy were transitioned to sacubitril-valsartan. The primary end point was the change in left ventricular (LV) volume at 1 year as assessed by 3-dimensional transthoracic echocardiography. Other echocardiographic end points included change in LV-function and change in right ventricular (RV) size and function. The mean age was 55 ± 12 years, and 63% were male. At 1 year, LV end-diastolic volume decreased from 242 ± 71 to 157 ± 57 ml (p <0.001) with a corresponding increase in LV ejection fraction from 32 ± 7% to 44 ± 9% (p <0.001). RV end-diastolic volume decreased from 151 ± 51 to 105 ±45 ml (p <0.001). Although RV ejection fraction did not change (51 ± 8 vs 51 ± 10; p = 0.35), RV global longitudinal strain improved from -14.9 ± 3.4 % to -19.3 ± 4.3% (p <0.001). When added to standard medical therapy for heart failure, sacubitril-valsartan induces significant remodeling of both the right and left ventricles as assessed by 3-dimensional echocardiography.

VE/VCO2 slope predicts RV dysfunction and mortality after left ventricular assist device: a fresh look at cardiopulmonary stress testing for prognostication.

Preoperative cardiopulmonary exercise testing (CPET) is well validated for prognostication before advanced surgical heart failure therapies, but its role in prognostication after LVAD surgery has never been studied. VE/VCO2 slope is an important component of CPET which has direct pathophysiologic links to right ventricular (RV) performance. We hypothesized that VE/VCO2 slope would prognosticate RV dysfunction after LVAD. All CPET studies from a single institution were collected between September 2009 and February 2019. Patients who ultimately underwent LVAD implantation were selectively analyzed. Peak VO2 and VE/VCO2 slope were measured for all patients. We evaluated their association with hemodynamic, echocardiographic and clinical markers of RV dysfunction as well mortality. Patients were stratified into those with a ventilatory class of III or greater. (VE/VCO2 slope of ≥ 36, n = 43) and those with a VE/VCO2 slope < 36 (n = 27). We compared the mortality between the 2 groups, as well as the hemodynamic, echocardiographic and clinical markers of RV dysfunction. 570 patients underwent CPET testing. 145 patients were ultimately referred to the advanced heart failure program and 70 patients later received LVAD implantation. Patients with VE/VCO2 slope of ≥ 36 had higher mortality (30.2% vs. 7.4%, p = 0.02) than patients with VE/VCO2 slope < 36 (n = 27). They also had a higher incidence of clinically important RVF (Acute severe 9.3% vs. 0%, Severe 32.6% vs 25.9%, p = 0.03). Patients with a VE/VCO2 slope ≥ 36 had a higher CVP than those with a lower VE/VCO2 slope (11.2 ± 6.1 vs. 6.0 ± 4.8 mmHg, p = 0.007), and were more likely to have a RA/PCWP ≥ 0.63 (65% vs. 19%, p = 0.008) and a PAPI ≤ 2 (57% vs. 13%, p = 0.008). In contrast, peak VO2 < 12 ml/kg/min was not associated with postoperative RV dysfunction or mortality. Elevated preoperative VE/VCO2 slope is a predictor of postoperative mortality, and is associated with postoperative clinical and hemodynamic markers of impaired RV performance.

Three-Dimensional Echocardiographic Left Atrial Appendage Volumetric Analysis.

BACKGROUND: Left atrial appendage (LAA) echocardiographic assessment is difficult because of the complex shape and relatively small size of the LAA. Three-dimensional (3D) echocardiographic imaging can overcome the limitations of two-dimensional imaging. Pulsed-wave Doppler is the only currently standard LAA functional parameter. The aim of this study was to test a new approach for 3D echocardiographic volumetric analysis to obtain LAA ejection fraction (EF), its size and shape. METHODS: Transesophageal two-dimensional and 3D LAA images were prospectively obtained in 159 consecutive patients. LAA volumes were measured from 3D echocardiographic images using available software. Pulsed-wave Doppler was considered the reference value for LAA function and was used for comparison with LAA EF. Comparison with cardiac computed tomography was performed in a subgroup of 32 patients. Comparisons included linear regression and Bland-Altman analyses. Repeated measurements were performed to assess measurement variability. RESULTS: Nine patients were excluded because of suboptimal image quality (94% feasibility). Three-dimensional LAA calculated EF was in good agreement with LAA pulsed-wave measurements. Three-dimensional morphologic evaluation showed that 43% of the patients had "chicken wing," 33% "cactus," 19% "windsock," and 5% cauliflower shapes. At the time of data acquisition, patients with atrial fibrillation had nonsignificantly larger LAA end-systolic and end-diastolic volumes, leading to lower calculated EFs. Three-dimensional echocardiographic LAA end-systolic volumes were in good agreement with cardiac computed tomography (r = 0.75), with small biases (mean, -2.5 ± 3.9 ml). Reproducibility was better for larger LAA volumes. CONCLUSIONS: A novel 3D echocardiographic approach can determine the geometry, size, and function of the LAA. A new parameter, LAA EF, provides functional quantitation.

Quantification of Right Ventricular Size and Function from Contrast-Enhanced Three-Dimensional Echocardiographic Images.

BACKGROUND: Three-dimensional (3D) echocardiography directly assesses right ventricular (RV) volumes without geometric assumptions, despite the complex shape of the right ventricle, and accordingly is more accurate and reproducible than the two-dimensional methodology, which is able to measure only surrogate parameters of RV function. Volumetric analysis has been hampered by frequent inability to clearly visualize RV endocardium, especially the RV free wall, in 3D echocardiographic images. The aim of this study was to test the hypothesis that RV contrast enhancement during 3D echocardiographic imaging would improve the accuracy of RV volume and function analysis. METHODS: Thirty patients with a wide range of RV size and function and image quality underwent transthoracic 3D echocardiography with and without contrast enhancement and cardiovascular magnetic resonance imaging on the same day. RV end-diastolic and end-systolic volumes and ejection fraction were measured from contrast-enhanced and nonenhanced 3D echocardiographic images and compared with cardiovascular magnetic resonance reference values using linear regression and Bland-Altman analyses. Blinded repeated measurements were performed to assess measurement variability. RESULTS: RV contrast enhancement was feasible in all patients. RV volumes obtained both with and without contrast enhancement correlated highly with cardiovascular magnetic resonance (end-diastolic volume, r = 0.90 and r = 0.92; end-systolic volume, r = 0.92 and r = 0.94, respectively), but the correlation for ejection fraction was better with contrast (r = 0.87 vs r = 0.70). Biases were smaller with contrast for all three parameters (end-diastolic volume, -16 ± 23 vs -36 ± 25 mL; end-systolic volume, -10 ± 16 vs -23 ± 18 mL; ejection fraction, -0.7 ± 5.5% vs -2.7 ± 8.1% of the mean measured values), reflecting improved accuracy. Also, measurement reproducibility was improved by contrast enhancement. CONCLUSIONS: Contrast enhancement improves the visualization of RV endocardial borders, resulting in more accurate and reproducible 3D echocardiographic measurements of RV size and function. This approach may be particularly useful in patients with suboptimal image quality.

Right Heart Involvement in Patients with Sarcoidosis.

The left ventricle (LV) is affected in 20-25% of patients with sarcoidosis and its involvement is associated with morbidity and mortality. However, effects of sarcoidosis on the right ventricle (RV) are not well documented. Our aims were to investigate the prevalence of RV dysfunction in patients with sarcoidosis and determine whether it is predominantly associated with direct cardiac involvement, severity of lung disease, or pulmonary hypertension (PH). We identified 50 patients with biopsy-proven extra-cardiac sarcoidosis and preserved LV function, who underwent echocardiography, pulmonary function (PF) testing, and cardiovascular magnetic resonance. RV function was quantified by free wall longitudinal strain. Tricuspid valve Doppler and estimated right atrial pressure were used to estimate systolic pulmonary artery pressure. Myocardial late gadolinium enhancement was considered diagnostic for cardiac sarcoidosis and assumed to involve both ventricles. Of the 50 patients, 28 (56%) had RV dysfunction, 4 with poorly defined PF status. Of the remaining 24 patients, 16 (67%) had lung disease, 8 (33%) had PH, and 10 (42%) had LV involvement. Ten patients had greater than one of these findings, and 4 had all 3. In contrast, in 4/24 patients (17%), RV dysfunction could not be explained by these mechanisms, despite severely reduced RV strain. In conclusion, RV dysfunction is common in patients with sarcoidosis and is usually associated with either direct LV involvement, lung disease, or PH, but may occur in the absence of these mechanisms, suggesting the possibility of isolated RV involvement and underscoring the need for imaging protocols that would include RV strain analysis.

The significance of pulmonary arterial hypertension pre- and post-transfemoral aortic valve implantation for severe aortic stenosis.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become the treatment of choice for the symptomatic patients with aortic stenosis (AS) and high surgical risk. Pulmonary hypertension (PHTN) has been shown to be associated with worse early and late outcomes after aortic valve surgery. Data regarding the effect of TAVI on PHTN are limited. METHODS AND RESULTS: We evaluated the characteristics and outcome of the patients with various degrees of systolic PHTN referred for TAVI. PHTN was defined as systolic pulmonary arterial pressure (SPAP) ≥50mmHg as assessed by echocardiography. The patients with SPAP decrease after TAVI to below 50mmHg were compared to the patients with persistent PHTN following TAVI. Of the 122 patients included in the present study, 49 (40%) patients had elevated SPAP prior to TAVI. This group of patients presented with smaller aortic valve areas, greater degrees of mitral or tricuspid regurgitation, lower left ventricular ejection fraction, and more prevalent chronic obstructive pulmonary disease (COPD) (all p<0.05). Following TAVI, 57% of the patients with prior PHTN experienced a reduction in SPAP to below 50mmHg. Multivariable analysis identified COPD to be the most powerful predictor for PHTN presence post-TAVI (hazard ratio 3.9, 95% confidence interval 1.5-9.9, p=0.005). Post-TAVI PHTN (SPAP ≥50mmHg) was associated with a 3.4-fold, independent, 2-year mortality risk (p=0.04). CONCLUSIONS: Our data suggest that TAVI is associated with a significant reduction in pulmonary pressure in more than half of the patients with preprocedural PHTN. COPD identifies the patients with persistent PHTN after TAVI. Post-TAVI PHTN is associated with markedly worse outcome.

Relation between stroke volume index to risk of death in patients with low-gradient severe aortic stenosis and preserved left ventricular function.

The aim of the present study was to evaluate whether assessment of stroke volume index (SVI) can be used to improve risk stratification among patients with low-gradient severe aortic stenosis and preserved ejection fraction (EF). Study population comprised 409 patients with aortic valve area ≤1.00 cm(2), mean gradient <40 mm Hg, and a normal EF (≥50%) who were followed up in a tertiary referral center from 2004 to 2012. Echocardiographic parameters and clinical data were collected. Multivariate Cox proportional hazards regression modeling was used to evaluate the association between SVI and the risk of all-cause mortality. Mean age of study patients was 78 ± 11 years, and 42% were men. The mean SVI was 39 ± 7 ml/m(2) (tertile 1 = 32 ± 4 ml/m(2); tertile 2 = 39 ± 1 ml/m(2); tertile 3 = 47 ± 4 ml/m(2)). Multivariate analysis showed that the SVI was the most powerful echocardiographic parameter associated with long-term outcome: each 5 ml/m(2) reduction in SVI was associated with a 20% increase in adjusted mortality risk (p = 0.01). Consistently, Kaplan-Meier analysis showed that the cumulative probability of survival during 3 years of follow-up was 60%, 72%, and 73% among patients in the low-, intermediate-, and high-SVI groups, respectively (p = 0.012). Our findings suggest that in patients with low-gradient severe aortic stenosis and preserved EF, there is a graded inverse relation between SVI and the risk of long-term mortality.

Bezafibrate treatment is associated with a reduced rate of re-hospitalization in smokers after acute coronary syndrome.

BACKGROUND: Significantly increased rate of hospitalizations in current smokers is a major smoking-related problem which is associated with a heavy economic burden, whereas cardiovascular disease accounted for nearly half of hospitalizations. The effect of bezafibrate on the rate of re-hospitalization in smokers already treated with statin immediately post-acute coronary syndrome (ACS) is unknown. The aim of this study was to investigate 30-day rate of re-hospitalization in current smokers participating in the ACS Israeli Surveys (ACSIS) and who were treated on discharge with a bezafibrate/statin combination vs. statin alone. METHODS: The study population comprised 3392 patients with confirmed current smoking status from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 3189 (94%) were discharged with statin alone, 203 (6%) with a combination of a statin and bezafibrate. RESULTS: Thirty-day re-hospitalization rate was significantly lower in patients from the combination group than in their counterparts from the statin monotherapy group: 12.8% vs. 19%, p = 0.028. Multivariable analysis identified the combined bezafibrate/statin treatment as an independent predictor of reduced risk of 30-day re-hospitalization rate with odds ratio (OR) 0.53 (95% confidence interval [CI] 0.31-0.91), and it corresponded to 47% risk reduction. Other significant variables in our model associated with independent risk of 30-day re-hospitalization rate during the follow-up were female gender (OR 1.43, CI 1.05-1.95, p = 0.03) and age > 65 years (OR 1.49, CI 1.13-1.95, p = 0.004). CONCLUSIONS: Adding bezafibrate to statin in smokers was associated with a significantly reduced 30-day rate of re-hospitalization after ACS.

Transcatheter aortic valve implantation for pure severe native aortic valve regurgitation.

OBJECTIVES: This study sought to collect data and evaluate the anecdotal use of transcatheter aortic valve implantation (TAVI) in pure native aortic valve regurgitation (NAVR) for patients who were deemed surgically inoperable BACKGROUND: Data and experience with TAVI in the treatment of patients with pure severe NAVR are limited. METHODS: Data on baseline patient characteristics, device and procedure parameters, echocardiographic parameters, and outcomes up to July 2012 were collected retrospectively from 14 centers that have performed TAVI for NAVR. RESULTS: A total of 43 patients underwent TAVI with the CoreValve prosthesis (Medtronic, Minneapolis, Minnesota) at 14 centers (mean age, 75.3 ± 8.8 years; 53% female; mean logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation), 26.9 ± 17.9%; and mean Society of Thoracic Surgeons score, 10.2 ± 5.3%). All patients had severe NAVR on echocardiography without aortic stenosis and 17 patients (39.5%) had the degree of aortic valvular calcification documented on CT or echocardiography. Vascular access was transfemoral (n = 35), subclavian (n = 4), direct aortic (n = 3), and carotid (n = 1). Implantation of a TAVI was performed in 42 patients (97.7%), and 8 patients (18.6%) required a second valve during the index procedure for residual aortic regurgitation. In all patients requiring second valves, valvular calcification was absent (p = 0.014). Post-procedure aortic regurgitation grade I or lower was present in 34 patients (79.1%). At 30 days, the major stroke incidence was 4.7%, and the all-cause mortality rate was 9.3%. At 12 months, the all-cause mortality rate was 21.4% (6 of 28 patients). CONCLUSIONS: This registry analysis demonstrates the feasibility and potential procedure difficulties when using TAVI for severe NAVR. Acceptable results may be achieved in carefully selected patients who are deemed too high risk for conventional surgery, but the possibility of requiring 2 valves and leaving residual aortic regurgitation remain important considerations.