Jutta Bergler-Klein

Natural History of Very Severe Aortic Stenosis

Background— We sought to assess the outcome of asymptomatic patients with very severe aortic stenosis. Methods and Results— We prospectively followed 116 consecutive asymptomatic patients (57 women; age, 67±16 years) with very severe isolated aortic stenosis defined by a peak aortic jet velocity (AV-Vel) ≥5.0 m/s (average AV-Vel, 5.37±0.35 m/s; valve area, 0.63±0.12 cm2). During a median follow-up of 41 months (interquartile range, 26 to 63 months), 96 events occurred (indication for aortic valve replacement, 90; cardiac deaths, 6). Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. AV-Vel but not aortic valve area was shown to independently affect event-free survival. Patients with an AV-Vel ≥5.5 m/s had an event-free survival of 44%, 25%, 11%, and 4% at 1, 2, 3, and 4 years, respectively, compared with 76%, 43%, 33%, and 17% for patients with an AV-Vel between 5.0 and 5.5 m/s (P<0.0001). Six cardiac deaths occurred in previously asymptomatic patients (sudden death, 1; congestive heart failure, 4; myocardial infarction, 1). Patients with an initial AV-Vel ≥5.5 m/s had a higher likelihood (52%) of severe symptom onset (New York Heart Association or Canadian Cardiovascular Society class >II) than those with an AV-Vel between 5.0 and 5.5 m/s (27%; P=0.03). Conclusions— Despite being asymptomatic, patients with very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration. Early elective valve replacement surgery should therefore be considered in these patients.

Comparison Between Transcatheter and Surgical Prosthetic Valve Implantation in Patients With Severe Aortic Stenosis and Reduced Left Ventricular Ejection Fraction

Background— Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis with conservative therapy but a high operative mortality when treated surgically. Recently, transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement (SAVR) for patients considered at high or prohibitive operative risk. The objective of this study was to compare TAVI and SAVR with respect to postoperative recovery of LVEF in patients with severe aortic stenosis and reduced LV systolic function. Methods and Results— Echocardiographic data were prospectively collected before and after the procedure in 200 patients undergoing SAVR and 83 patients undergoing TAVI for severe aortic stenosis (aortic valve area ≤1 cm2) with reduced LV systolic function (LVEF ≤50%). TAVI patients were significantly older (81±8 versus 70±10 years; P<0.0001) and had more comorbidities compared with SAVR patients. Despite similar baseline LVEF (34±11% versus 34±10%), TAVI patients had better recovery of LVEF compared with SAVR patients (&Dgr;LVEF, 14±15% versus 7±11%; P=0.005). At the 1-year follow-up, 58% of TAVI patients had a normalization of LVEF (>50%) as opposed to 20% in the SAVR group. On multivariable analysis, female gender (P=0.004), lower LVEF at baseline (P=0.005), absence of atrial fibrillation (P=0.01), TAVI (P=0.007), and larger increase in aortic valve area after the procedure (P=0.01) were independently associated with better recovery of LVEF. Conclusion— In patients with severe aortic stenosis and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with SAVR. TAVI may provide an interesting alternative to SAVR in patients with depressed LV systolic function considered at high surgical risk.

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients With Acute Myocardial Infarction Based on Individual Patient Data

RATIONALE The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. OBJECTIVE We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). METHODS AND RESULTS The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. CONCLUSIONS This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.

Predictors of Outcomes in Low-Flow, Low-Gradient Aortic Stenosis Results of the Multicenter TOPAS Study

Background— Patients with low-flow, low-gradient aortic stenosis have a poor prognosis with conservative therapy but a high operative mortality if treated surgically. Recently, we proposed a new index of aortic stenosis severity derived from dobutamine stress echocardiography, the projected aortic valve area at a normal transvalvular flow rate, as superior to other conventional indices to differentiate true-severe from pseudosevere aortic stenosis. The objective of this study was to identify the determinants of survival, functional status, and change in left ventricular ejection fraction during follow-up of patients with low-flow, low-gradient aortic stenosis. Methods and Results— One hundred one patients with low-flow, low-gradient aortic stenosis (aortic valve area ≤1.2 cm2, left ventricular ejection fraction ≤40%, and mean gradient ≤40 mm Hg) underwent dobutamine stress echocardiography and an assessment of functional capacity using the Duke Activity Status Index. A subset of 72 patients also underwent a 6-minute walk test. Overall survival was 70±5% at 1 year and 57±6% at 3 years. After adjusting for age, gender, and the type of treatment (aortic valve replacement versus no aortic valve replacement), significant predictors of mortality during follow-up were a Duke Activity Status Index ≤20 (P=0.0005) or 6-minute walk test distance ≤320 m (P<0.0001, in the subset of 72 patients), projected aortic valve area at a normal transvalvular flow rate ≤1.2 cm2 (P=0.03), and peak dobutamine stress echocardiography left ventricular ejection fraction ≤35% (P=0.03). More severe stenosis, defined as projected aortic valve area ≤1.2 cm2, was a predictor of mortality only in the no aortic valve replacement group. The Duke Activity Status Index, 6-minute walk test, and left ventricular ejection fraction improved significantly during follow-up in the aortic valve replacement group, but remained unchanged or decreased in the no aortic valve replacement group. Conclusion— In patients with low-flow, low-gradient aortic stenosis, the most significant risk factors for poor outcome were (1) impaired functional capacity as measured by Duke Activity Status Index or 6-minute walk test distance; (2) more severe valve stenosis as measured by projected aortic valve area at a normal transvalvular flow rate; and (3) reduced peak stress left ventricular ejection fraction, a composite measure accounting for both resting left ventricular function and contractile reserve.

Plasma big endothelin-1 concentrations in congestive heart failure patients with or without systemic hypertension

Plasma endothelin concentrations were evaluated in 53 chronic, congestive heart failure (CHF) patients with or without history of systemic hypertension, as well as in 9 with hypertension only and in 22 healthy control subjects. Plasma renin, aldosterone and atrial natriuretic peptide, as well as clinical and hemodynamic data were determined. In patients with CHF, big endothelin-1 was, independent of hypertension history, significantly greater than in hypertensive patients with normal cardiac function and in control subjects (both p < 0.0001). Patients with severe CHF had significantly greater big endothelin-1 values than did those with moderate CHF. During 12-month follow-up, 11 patients with CHF underwent heart transplantation, and 9 died; these patients had significantly greater big endothelin-1 concentrations than did the 33 clinically stable patients (p < 0.001). Big endothelin-1 and atrial natriuretic peptide correlated with right atrial pressure, pulmonary capillary wedge pressure, left ventricular ejection fraction, effort capacity and severity of CHF (New York Heart Association functional class).

B-type natriuretic peptide in low-flow, low-gradient aortic stenosis : Relationship to hemodynamics and clinical outcome: Results from the multicenter truly or pseudo-severe aortic stenosis (TOPAS) study

Background— The prognostic value of B-type natriuretic peptide (BNP) is unknown in low-flow, low-gradient aortic stenosis (AS). We sought to evaluate the relationship between AS and rest, stress hemodynamics, and clinical outcome. Methods and Results— BNP was measured in 69 patients with low-flow AS (indexed effective orifice area <0.6 cm2/m2, mean gradient ≤40 mm Hg, left ventricular ejection fraction ≤40%). All patients underwent dobutamine stress echocardiography and were classified as truly severe or pseudosevere AS by their projected effective orifice area at normal flow rate of 250 mL/s (effective orifice area ≤1.0 cm2 or >1.0 cm2). BNP was inversely related to ejection fraction at rest (Spearman correlation coefficient rs=−0.59, P<0.0001) and at peak stress (rs=−0.51, P<0.0001), effective orifice area at rest (rs=−0.50, P<0.0001) and at peak stress (rs=−0.46, P=0.0002), and mean transvalvular flow (rs=−0.31, P=0.01). BNP was directly related to valvular resistance (rs=0.42, P=0.0006) and wall motion score index (rs=0.36, P=0.004). BNP was higher in 29 patients with truly severe AS versus 40 with pseudosevere AS (median, 743 pg/mL [Q1, 471; Q3, 1356] versus 394 pg/mL [Q1, 191 to Q3, 906], P=0.012). BNP was a strong predictor of outcome. In the total cohort, cumulative 1-year survival of patients with BNP ≥550 pg/mL was only 47±9% versus 97±3% with BNP <550 (P<0.0001). In 29 patients who underwent valve replacement, postoperative 1-year survival was also markedly lower in patients with BNP ≥550 pg/mL (53±13% versus 92±7%). Conclusions— BNP is significantly higher in truly severe than pseudosevere low-gradient AS and predicts survival of the whole cohort and in patients undergoing valve replacement.

Validation of Conventional and Simplified Methods to Calculate Projected Valve Area at Normal Flow Rate in Patients With Low Flow, Low Gradient Aortic Stenosis: The Multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) Study

BACKGROUND It has been previously demonstrated that a new index of aortic stenosis (AS) severity derived from dobutamine stress echocardiography (DSE), the projected aortic valve area (AVA) at a normal transvalvular flow rate (AVA(proj)), is superior to traditional Doppler echocardiographic indices to discriminate true severe from pseudosevere low-gradient AS. The objectives of this study were to prospectively validate the diagnostic and prognostic value of AVA(proj) in a large series of patients and to propose a new clinically applicable simplified method to estimate AVA(proj). METHODS AVA(proj) was calculated in 142 patients with low-flow AS using 2 methods. In the conventional method, AVA was plotted against mean transvalvular flow (Q) at each stage of DSE, and AVA at a standardized flow rate of 250 ml/s was projected from the slope of the regression line fitting the plot of AVA versus Q: AVA(proj) = AVA(rest) + slope x (250 - Q(rest)). In the simplified method, using this equation, the slope of the regression line was estimated by dividing the DSE-induced change in AVA from baseline to the peak stage of DSE by the change in Q. RESULTS There was a strong correlation between AVA(proj) calculated by the two methods (r = 0.95, P < .0001). Among the 142 patients, 52 underwent aortic valve replacement and had underlying AS severity assessed by the surgeon. Conventional and simplified AVA(proj) demonstrated similar performance in discriminating true severe from pseudosevere AS (percentage of correct classification of AVA(proj) < or = 1 cm(2), 94% and 92%, respectively) and were superior to traditional dobutamine stress echocardiographic indices (percentage of correct classification, 60%-77%). Both conventional and simplified AVA(proj) correlated well with valve weight (r = 0.52 and r = 0.58, respectively), whereas traditional dobutamine stress echocardiographic indices did not. In the 84 patients who were treated medically, conventional AVA(proj) < or = 1.2 cm(2) (hazard ratio, 1.65; P = .02) and simplified AVA(proj) < or = 1.2 cm(2) (hazard ratio, 2.70; P < .0001) were independent predictors of mortality. Traditional dobutamine stress echocardiographic indices were not predictive. CONCLUSION In patients with low-flow AS, AVA(proj) better predicts underlying AS severity and patient outcomes than traditional dobutamine stress echocardiographic indices. Simplified AVA(proj) is easier to calculate than conventional AVA(proj), facilitating the use of AVA(proj) in clinical practice.

Cell therapy for human ischemic heart diseases: Critical review and summary of the clinical experiences

A decade ago, stem or progenitor cells held the promise of tissue regeneration in human myocardium, with the expectation that these therapies could rescue ischemic myocyte damage, enhance vascular density and rebuild injured myocardium. The accumulated evidence in 2014 indicates, however, that the therapeutic success of these cells is modest and the tissue regeneration involves much more complex processes than cell-related biologics. As the quest for the ideal cell or combination of cells continues, alternative cell types, such as resident cardiac cells, adipose-derived or phenotypic modified stem or progenitor cells have also been applied, with the objective of increasing both the number and the retention of the reparative cells in the myocardium. Two main delivery routes (intracoronary and percutaneous intramyocardial) of stem cells are currently used preferably for patients with recent acute myocardial infarction or ischemic cardiomyopathy. Other delivery modes, such as surgical or intravenous via peripheral veins or coronary sinus have also been utilized with less success. Due to the difficult recruitment of patients within conceivable timeframe into cardiac regenerative trials, meta-analyses of human cardiac cell-based studies have tried to gather sufficient number of subjects to present a statistical compelling statement, reporting modest success with a mean increase of 0.9-6.1% in left ventricular global ejection fraction. Additionally, nearly half of the long-term studies reported the disappearance of the initial benefit of this treatment. Beside further extensive efforts to increase the efficacy of currently available methods, pre-clinical experiments using new techniques such as tissue engineering or exploiting paracrine effect hold promise to regenerate injured human cardiac tissue.

Usefulness of Global Left Ventricular Longitudinal Strain for Risk Stratification in Low Ejection Fraction, Low-Gradient Aortic Stenosis Results From the Multicenter True or Pseudo-Severe Aortic Stenosis Study

Background—The objective of this study was to examine the impact of left ventricular (LV) global longitudinal strain (GLS) measured at rest and at dobutamine stress echocardiography on the outcome of patients with low LV ejection fraction and low-gradient aortic stenosis. Methods and Results—Among the 202 patients with low LV ejection fraction (⩽40%), low-gradient aortic stenosis (mean transvalvular gradient <40 mm Hg and indexed aortic valve area ⩽0.6 cm2/m2) prospectively enrolled in the multicenter True or Pseudo-Severe Aortic Stenosis study, 126 patients with resting GLS and 73 patients with stress GLS available were included in this substudy. Three-year survival rate was 49% in patients with rest GLS <|9|% compared with 68% in patients with GLS >|9|% (P=0.02). In a multivariable Cox model adjusted for age, coronary artery disease, projected aortic valve area at a normal flow rate and type of treatment (aortic valve replacement versus conservative), rest GLS <|9|% (hazard ratio, 2.18; P=0.015) remained independently associated with all-cause mortality. GLS <|10|% measured during dobutamine stress echocardiography was also independently associated with mortality (hazard ratio, 2.67; P=0.01). In the subset of patients with stress GLS (n=73), the &khgr;2 of the multivariable model to predict all-causes mortality was 21.96 for stress GLS versus 17.78 for rest GLS. Conclusions—GLS is independently associated with mortality in patients with low LV ejection fraction, low-gradient aortic stenosis. Stress GLS measured during dobutamine stress echocardiography may provide incremental prognostic value beyond GLS measured at rest. Hence, measurement of GLS at rest and during dobutamine stress echocardiography may be helpful to enhance risk stratification in low LV ejection fraction, low-gradient aortic stenosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835028.

Prognostic value of serial B-type natriuretic peptide measurement in asymptomatic organic mitral regurgitation

Optimal timing of surgery is crucial in mitral regurgitation (MR) to avoid excess mortality and morbidity. The role of brain‐type natriuretic peptide (BNP) in this setting remains controversial. We evaluated the value of serial BNP measurements for early prediction of deterioration in asymptomatic MR.