Pellikka, Patricia A

Background— In asymptomatic patients with severe aortic stenosis, guidelines recommend left ventricular ejection fraction (LVEF) of <50% as the threshold for referral for aortic valve replacement. We investigated the importance of LVEF on long-term outcome after aortic valve replacement in symptomatic and asymptomatic patients with severe aortic stenosis. Methods and Results— We retrospectively identified 2017 patients with severe aortic stenosis (aortic valve area<1 cm 2 , mean gradient≥40 mm Hg, or indexed aortic valve area<0.6 cm 2 /m 2 ) who underwent surgical aortic valve replacement from January 1995 to June 2009. Patients were divided into 4 groups depending on preoperative LVEF (<50% in 300 [15%] patients, 50%–59% in 331 [17%], 60%–69% in 908 [45%], and ≥70% in 478 [24%]). During follow-up of 5.3±4.4 years, 1056 (52%) patients died. A decrease in mortality was observed with increasing LVEF, P <0.0001; 5-year mortality estimates (95% confidence interval) were 0.41 (0.35–0.47), LVEF<50%; 0.35 (0.29–0.41), LVEF 50% to 59%; 0.26 (0.23–0.29), LVEF 60% to 69%; and 0.22 (0.18–0.26), LVEF≥70%. Compared with patients with LVEF≥60%, patients with LVEF 50% to 59% had increased mortality (hazard ratio [HR], 1.58; P <0.001), with similar risk increase in both symptomatic (HR, 1.56; P <0.001) and asymptomatic patients (HR, 1.58; P =0.006). Correcting for risk factors, LV mass index, aortic valve area, and stroke volume index, LVEF was independently predictive of mortality (HR, 0.88 per 10%; P <0.001). When this analysis was repeated in the subset of 1333 patients without history of coronary artery disease, LVEF remained associated with mortality (HR, 0.90 per 10%; P =0.009). Conclusions— LVEF is a powerful predictor of outcome in patients with severe aortic stenosis undergoing aortic valve replacement, independent of the presence of valve-related symptoms.

Background Myocardial strain imaging is a sensitive echocardiographic technique for identifying ventricular dysfunction. The aim of this study was to describe a reference range for right ventricular ( RV ) strain in subjects without cardiopulmonary disease and to report these values from a systematic review and meta‐analysis of the current literature. Methods Prospective online measurement of RV free wall longitudinal systolic strain using speckle tracking echocardiography ( STE ) was performed in 116 subjects with normal echocardiograms and without cardiopulmonary disease or risk factors. A systematic search of studies in EMBASE and Medline reporting RV strain values was performed through February 2014. Results The mean age was 48 ± 16 years and 58% were female. Mean RV strain was −26 ± 4%. Ten studies involving a total of 486 patients met our inclusion criteria. The mean age range was 43–57 years and 59% were female. All prior studies were performed with offline strain analysis, and 9 used a GE Healthcare strain analysis software system. The weighted estimate of RV free wall strain measured using tissue Doppler imaging (4 studies) was −27 ± 1% (95% confidence interval [ CI ] −30% to −25%) and with STE (8 studies, including the current study data) −27 ± 2% (95% CI −29% to −24%), respectively. Conclusions A reference range for RV strain in subjects without cardiopulmonary disease is presented. These data may help facilitate the routine clinical measurement of RV strain in patients referred for right heart echocardiography assessment.

Background— In aortic valve stenosis (AS), the occurrence of heart failure symptoms does not always correlate with severity of valve stenosis and left ventricular (LV) function. Therefore, we tested the hypothesis that symptomatic patients with AS have impaired diastolic, longitudinal systolic function, and left atrial dilatation compared with asymptomatic patients. Methods and Results— In a retrospective descriptive study, we compared clinical characteristics and echocardiographic parameters in 99 symptomatic and 139 asymptomatic patients with severe AS and LV ejection fraction ≥50%. Independent predictors of symptomatic state were identified using logistic regression analysis. Symptomatic patients were younger (72±10 versus 76±12 years of age; P =0.002), presented less often with atrial fibrillation (13% versus 24%; P =0.05) and chronic obstructive pulmonary disease (2% versus 19%; P <0.001), and had a lower prevalence of hypertension (73% versus 40%; P <0.001). Despite similar AS severity, symptomatic patients had higher LV mass index (120±39 versus 95±25 g/m 2 ; P <0.0001), increased relative wall thickness (0.61±0.15 versus 0.50±0.11; P <0.0001), shorter mitral deceleration time (199±58 versus 268±62 ms; P <0.0001), and increased left atrial volume index (49±18 versus 42±15 mL/m 2 ; P =0.02). When adjusting for age, history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease in a multivariable logistic regression analysis, LV mass index, relative wall thickness, left atrial volume index, and deceleration time were still associated with the presence of symptoms. Conclusions— The present study demonstrates that symptomatic status in severe AS is associated with impaired diastolic function, LV hypertrophy, concentric remodeling, and left atrial dilatation when corrected for indices of AS severity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00294775.

Background— Among patients with severe aortic stenosis (AS) and preserved ejection fraction, those with low gradient (LG) and reduced stroke volume may have an adverse prognosis. We investigated the prognostic impact of stroke volume using the recently proposed flow-gradient classification. Methods and Results— We examined 1704 consecutive patients with severe AS (aortic valve area <1.0 cm 2 ) and preserved ejection fraction (≥50%) using 2-dimensional and Doppler echocardiography. Patients were stratified by stroke volume index (<35 mL/m 2 [low flow, LF] versus ≥35 mL/m 2 [normal flow, NF]) and aortic gradient (<40 mm Hg [LG] versus ≥40 mm Hg [high gradient, HG]) into 4 groups: NF/HG, NF/LG, LF/HG, and LF/LG. NF/LG (n=352, 21%), was associated with favorable survival with medical management (2-year estimate, 82% versus 67% in NF/HG; P <0.0001). LF/LG severe AS (n=53, 3%) was characterized by lower ejection fraction, more prevalent atrial fibrillation and heart failure, reduced arterial compliance, and reduced survival (2-year estimate, 60% versus 82% in NF/HG; P <0.001). In multivariable analysis, the LF/LG pattern was the strongest predictor of mortality (hazard ratio, 3.26; 95% confidence interval, 1.71–6.22; P <0.001 versus NF/LG). Aortic valve replacement was associated with a 69% mortality reduction (hazard ratio, 0.31; 95% confidence interval, 0.25–0.39; P <0.0001) in LF/LG and NF/HG, with no survival benefit associated with aortic valve replacement in NF/LG and LF/HG. Conclusions— NF/LG severe AS with preserved ejection fraction exhibits favorable survival with medical management, and the impact of aortic valve replacement on survival was neutral. LF/LG severe AS is characterized by a high prevalence of atrial fibrillation, heart failure, and reduced survival, and aortic valve replacement was associated with improved survival. These findings have implications for the evaluation and subsequent management of AS severity.

Background— Although right ventricular (RV) dysfunction is a major determinant of outcome in patients with pulmonary hypertension (PH), the optimal measure of RV function is poorly defined. We hypothesized that RV strain measured by speckle-tracking echocardiography predicts outcome in PH over a broad range of pulmonary pressures. Methods and Results— Prospective peak RV longitudinal systolic strain measurement was performed on 575 patients (mean age, 56±18 years; 63% women) referred for echocardiography for known or suspected PH. Survival status was assessed over a median of 16.5 (interquartile range, 7.6–20.0) months. There were 406 patients with PH (71%) (74% group 1, 14% group 3, and 12% group 4) and 169 patients without evidence of PH (29%). Among patients with PH, 46% were World Health Organization functional class III–IV. The mean RV strain was −21.2±6.7% for all patients. RV strain declined with worse functional class, shorter 6-minute walk distances, higher N-terminal pro-B-type natriuretic peptide levels, and the presence of right heart failure. RV strain predicted outcome across pulmonary pressures and groups of PH. Eighteen-month survival was 92%, 88%, 85%, and 71% according to RV strain quartile ( P <0.001), with a 1.46 higher risk of death (95% confidence interval, 1.05–2.12) per 6.7% decline in RV strain. RV strain predicted survival when adjusted for pulmonary pressure, pulmonary vascular resistance, and right atrial pressure and provided incremental prognostic value over conventional clinical and echocardiographic variables. Conclusions— Quantitative assessment of RV free-wall systolic strain is feasible and is a powerful predictor of the clinical outcome of patients with known or suspected PH.

Background— Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right heart failure. The right (RV) and left ventricles (LV) do not function in isolation, sharing a common pericardial sac and interventricular septum. We sought to define the clinical and prognostic significance of ventricular interdependence in PAH and its association with LV filling patterns through speckle-tracking strain echocardiography. Methods and Results— Echocardiography was performed in 71 adults with a new diagnosis of PAH. To analyze LV and RV function separately, we measured peak systolic longitudinal and circumferential strain of the LV and RV. Survival was assessed >2 years. Patients had dilated right-sided chambers (right atrial volume index, 44±19 mL/m 2 ; RV end-diastolic area, 34±9 cm 2 ), and reduced RV function (RV fractional area change, 28±12%). Speckle-tracking echocardiography revealed significant reductions in RV free wall peak systolic strain (−15±3%). Despite normal LV size and normal conventional measures of LV systolic function (end-diastolic dimension, 42±6 mm; ejection fraction, 65±8%; cardiac index, 2.6±0.8 L/min per m 2 ), patients had reduced LV free wall systolic strain (−15±3%). Decreased LV free wall systolic strain was associated with a delayed relaxation mitral inflow Doppler pattern, P =0.0002. During 2-year follow-up, 19 patients (27%) died. LV strain was associated with increased mortality (unadjusted hazard ratio, 2.40 per 5% decrease in LV free wall strain, 1.22–4.68), which remained significant when adjusted for age, sex, World Health Organization functional class, and PAH pathogenesis (hazard ratio, 3.11, 1.38–7.20). Conclusions— The pressure loading in PAH results in geometric alterations and functional decline of the RV, with marked reduction in RV systolic strain. Despite preservation of LV ejection fraction, LV systolic strain was also reduced and associated with early mortality, highlighting the significance of ventricular interdependence in PAH.

Background Plasma fibulin‐1 levels have been associated with N‐terminal pro–B‐type natriuretic peptide levels and left atrial size and shown to be predictive of mortality in patients with diabetes. The mechanisms behind these connections are not fully understood but are probably related to its roles as an extracellular matrix protein in cardiovascular tissues. Methods and Results One hundred twenty‐five patients with severe aortic stenosis who were scheduled for aortic valve replacement ( AVR ) were evaluated with preoperative echocardiography and their plasma fibulin‐1 levels were determined with ELISA . The cohort was followed for a median of 4 years after AVR . Increased restrictive left ventricular ( LV ) filling pattern was observed with increased plasma fibulin‐1 levels (2% versus 29% versus 24% in low, middle, and high plasma fibulin‐1 tertile groups, P =0.004). Likewise, reduced longitudinal systolic LV function (6.6±1.1 versus 6.1±1.3 versus 5.7±1.5 cm/s, P =0.05) and increased LV filling pressures was systolic velocity of the mitral annulus observed with increasing plasma fibulin‐1 concentrations (ratio of early transmitral flow velocity to early diastolic flow velocity of the mitral annulus 13±4 versus 15±5 versus 16±6 in the fibulin‐1 tertile groups, P =0.04). Conclusions In patients with symptomatic severe aortic stenosis undergoing AVR, plasma fibulin‐1 is associated with restrictive filling of the LV , decreased longitudinal systolic function of the LV , and increased LV filling pressures. Clinical Trial Registration URL: www.clinicaltrial.gov with Identifier: NCT00294775