Philipp E. Bartko

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.

Two-dimensional strain for the assessment of left ventricular function in low flow-low gradient aortic stenosis, relationship to hemodynamics, and outcome: a substudy of the multicenter TOPAS study.

Background— Decision making in patients with low flow–low gradient aortic stenosis mainly depends on the actual stenosis severity and left ventricular function, which is of prognostic importance. We used 2-dimensional strain parameters measured by speckle tracking at rest and during dobutamine stress echocardiography to document the extent of myocardial impairment, its relationship with hemodynamic variables, and its prognostic value. Methods and Results— In 47 patients with low flow–low gradient aortic stenosis, global peak systolic longitudinal strain (PLS) and peak systolic longitudinal strain rate (PLSR) were analyzed. PLS and PLSR at rest and peak stress were −7.56±2.34% and −7.41±2.89% (P=NS) and −0.38±0.12 s−1 and −0.53±0.18 s−1 (P<0.001), respectively. PLS and PLSR inversely correlated with left ventricular ejection fraction at rest (r s=−0.52; P<0.0001 and −0.38; P=0.008) and peak stress (r s=−0.39; P=0.007 and −0.45; P=0.002). The overall 2-year survival rate was 60%. Univariate predictors of survival were peak stress left ventricular ejection fraction (P=0.0026), peak stress PLS (P=0.0002), peak stress PLSR (P<0.0001), and N-terminal pro–B-type natriuretic peptide (P<0.0001). Three hierarchically nested multivariable Cox regression models were constructed—model 1: The Society of Thoracic Surgeons score as an indicator of clinical risk (area under the receiver operating characteristic=0.59); model 2: model 1+N-terminal pro–B-type natriuretic peptide and peak stress left ventricular ejection fraction (area under the receiver operating characteristic=0.83; incremental P<0.0001); model 3: model 2+peak stress PLSR (area under the receiver operating characteristic=0.89; incremental P=0.035). Conclusions— In patients with low flow–low gradient aortic stenosis, 2-dimensional strain parameters are strong predictors of outcome. Peak stress PLSR may add incremental prognostic value beyond what is obtained from N-terminal pro–B-type natriuretic peptide and peak stress left ventricular ejection fraction. A larger study is needed to confirm these findings.

Size matters! Impact of age, sex, height, and weight on the normal heart size.

Background—Therapeutic decisions in cardiology are determined frequently by cardiac chamber size. To decide whether cardiac dimensions are still in the normal range, reliable reference values are needed. However, published reference values mostly refer to historical cohorts using motion-mode measurements and have not been adjusted for sex or age. The impact of body size was only vaguely addressed. The importance of such adjustments is illustrated by studies, which show that smaller individuals and women are at risk of delayed treatment and impaired outcome when currently used reference values are applied. The aim of the present study was to assess the impact of body size, sex, and age on the normal heart size. Methods and Results—We prospectively studied 622 individuals (52.7% women; 17–91 years; 143–200 cm; 32–240 kg) without cardiac disease by standard transthoracic echocardiography. Multivariable linear regression analyses of the impact of sex, age, height, and weight on cardiac chamber size were performed. By multivariable regression analysis (n=500), all 4 variables independently influenced cardiac chamber size. The validity of cardiac dimensions predicted by the regression model was tested prospectively in a validation cohort (n=122). A calculator is proposed that estimates cardiac dimensions on the basis of the regression analysis. Conclusions—Sex, height, weight, and age significantly affect the normal heart size. These parameters need to be considered when cutoff values indicating the need for treatment or even surgery are established.

CD45 Expression in Mitral Valve Endothelial Cells After Myocardial Infarction.

RATIONALE Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation. OBJECTIVE Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro. METHODS AND RESULTS Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45+ endothelial cells (VE-cadherin+/CD45+/α-smooth muscle actin [SMA]+ and VE-cadherin+/CD45+/αSMA- cells) and possible fibrocytes (VE-cadherin-/CD45+/αSMA+) in inferior MI compared with sham-operated and normal sheep. CD45+ cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin+/CD45+/αSMA+ cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-β1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-β1 to 3, not observed in transforming growth factor-β1-treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells. CONCLUSIONS MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-β1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45+ endothelial cells to MV adaptation and fibrosis post MI warrants investigation.

Tricuspid Regurgitation Is Associated With Increased Risk of Mortality in Patients With Low-Flow Low-Gradient Aortic Stenosis and Reduced Ejection Fraction : Results of the Multicenter TOPAS Study (True or Pseudo-Severe Aortic Stenosis)

OBJECTIVES This study sought to examine the impact of tricuspid regurgitation (TR) on mortality in patients with low-flow, low-gradient (LF-LG) aortic stenosis (AS) and reduced left ventricular ejection fraction (LVEF). BACKGROUND TR is often observed in patients with LF-LG AS and low LVEF, but its impact on prognosis remains unknown. METHODS A total of 211 patients (73±10 years of age; 77% men) with LF-LG AS (mean gradient<40 mm Hg and indexed aortic valve area [AVA]≤0.6 cm2/m2) and reduced LVEF (≤40%) were prospectively enrolled in the TOPAS (True or Pseudo-Severe Aortic Stenosis) study and 125 (59%) of them underwent aortic valve replacement (AVR) within 3 months following inclusion. The severity of AS was assessed by the projected AVA (AVAproj) at normal flow rate (250 ml/s), as previously described and validated. The severity of TR was graded according to current guidelines. RESULTS Among the 211 patients included in the study, 22 (10%) had no TR, 113 (54%) had mild (grade 1), 50 (24%) mild-to-moderate (grade 2), and 26 (12%) moderate-to-severe (grade 3) or severe (grade 4) TR. During a mean follow-up of 2.4±2.2 years, 104 patients (49%) died. Univariable analysis showed that TR≥2 was associated with increased risk of all-cause mortality (hazard ratio [HR]: 1.82, 95% confidence interval [CI]: 1.22 to 2.71; p=0.004) and cardiovascular mortality (HR: 1.85, 95% CI: 1.20 to 2.83; p=0.005). After adjustment for age, sex, coronary artery disease, AVAproj, LVEF, stroke volume index, right ventricular dysfunction, mitral regurgitation, and type of treatment (AVR vs. conservative), the presence of TR≥2 was an independent predictor of all-cause mortality (HR: 1.88, 95% CI: 1.08 to 3.23; p=0.02) and cardiovascular mortality (HR: 1.92, 95% CI: 1.05 to 3.51; p=0.03). Furthermore, in patients undergoing AVR, TR≥3 was an independent predictor of 30-day mortality compared with TR=0/1 (odds ratio [OR]: 7.24, 95% CI: 1.56 to 38.2; p=0.01) and TR=2 (OR: 4.70, 95% CI: 1.00 to 25.90; p=0.05). CONCLUSIONS In patients with LF-LG AS and reduced LVEF, TR is independently associated with increased risk of cumulative all-cause mortality and cardiovascular mortality regardless of the type of treatment. In patients undergoing AVR, moderate/severe TR is associated with increased 30-day mortality. Further studies are needed to determine whether TR is a risk marker or a risk factor of mortality and whether concomitant surgical correction of TR at the time of AVR might improve outcomes for this high-risk population.

Right ventricular longitudinal strain for risk stratification in low-flow, low-gradient aortic stenosis with low ejection fraction

Background Left ventricular global longitudinal strain (LVLS) is a powerful predictor of outcome in patients with low-flow, low-gradient aortic stenosis (LF-LG AS) and low LV ejection fraction (LVEF). However, the impact of right ventricular (RV) function on the outcome of these patients remains unknown. Objectives The aim of this study was to examine the impact of RV function as evaluated by RV free wall longitudinal strain (RVLS) on mortality in patients with LF-LG AS and low LVEF. Methods 211 patients with LF-LG AS (mean gradient <40 mm Hg and indexed aortic valve area (AVA) ≤0.6 cm2/m2) and low LVEF (≤40%)) were prospectively recruited in the True or Pseudo-severe Aortic Stenosis study. AS severity was assessed using the projected AVA (AVAproj) at normal flow rate. Among the 211 patients, 128 had RVLS measurement available at rest and were included in this analysis. RVLS measurement at dobutamine stress echocardiography (DSE) was available in 58 of the 128 patients. Results Two-year survival was lower in patients with RVLS<|13|% (53%±9%) compared with those with RVLS>|13|% (69%±5%) (p=0.04). In multivariable Cox analysis stratified for the type of treatment (aortic valve replacement vs conservative) and adjusted for age, AS severity, previous myocardial infarction and LVLS, rest RVLS<|13|% (HR=2.70; 95% CI 1.19 to 6.11; p=0.018) was independently associated with all-cause mortality. RVLS had incremental prognostic value over baseline risk factors and LVLS (χ2=20.13 vs 13.56; p=0.01). Reduced stress RVLS was also associated with increased risk of mortality (stress RVLS<|14|%: HR=2.98; 95% CI 1.30 to 6.52; p=0.01). In multivariable Cox analysis, stress RVLS<|14|% remained independently associated with mortality (HR=2.94; 95% CI 1.23 to 7.02; p=0.015). After further adjustment for rest RVLS, stress RVLS<|14|% remained independently associated with mortality (HR=3.29; 95% CI 1.17 to 9.25; p=0.024), whereas rest RVLS was not (p>0.05). Conclusions In this series of patients with LF-LG AS and low LVEF, reduced RVLS was independently associated with increased risk of mortality. Furthermore, stress RVLS provided incremental prognostic value beyond that obtained from rest RVLS. Thus, RVLS measurement at rest and at DSE may be helpful to enhance risk stratification in this high-risk population. Trial registration number NCT01835028; Results.

Refining the prognostic impact of functional mitral regurgitation in chronic heart failure

Aims Significant efforts are currently undertaken to reduce functional mitral regurgitation (FMR) in patients with chronic heart failure in the hope to improve prognosis. We aimed to assess the prognostic impact of FMR in heart failure with reduced ejection fraction (HFrEF) under optimal medical therapy (OMT) and various conditions of HFrEF. We further intended to identify a heart failure phenotype, where FMR is most likely a driving force and not a mere bystander of the disease. Methods and results We prospectively included 576 consecutive HFrEF patients into our long-term observational study. Functional [i.e. New York Heart Association (NYHA) class], echocardiographic, invasive haemodynamic, and biochemical (i.e. NT-proBNP, MR-proANP, MR-proADM, CT-proET-1, copeptin) measurements were performed at baseline. During a median follow-up of 62 months (interquartile range 52-76), 47% of patients died. Severe FMR was a significant predictor of mortality [hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.34-2.30; P < 0.001], independent of clinical (adjusted HR 1.61, 95% CI 1.22-2.12; P = 0.001), and echocardiographic (adjusted HR 1.46, 95% CI 1.09-1.94; P = 0.01) confounders, OMT (adjusted HR 1.81, 95% CI 1.25-2.63; P = 0.002), and neurohumoral activation (adjusted HR 1.38, 95% CI 1.03-1.84; P = 0.03). Subanalysis revealed that severe FMR was associated with poor outcome in an intermediate-failure phenotype of HFrEF i.e. patients with NYHA class II (adjusted HR 2.17, 95% CI 1.07-4.44; P = 0.03) and III (adjusted HR 1.80, 95% CI 1.17-2.77; P = 0.008), moderately reduced left ventricular function (adjusted HR 2.37, 95% CI 1.36-4.12; P = 0.002), and within the second quartile (871-2360 pg/mL) of NT-proBNP (adjusted HR 2.16, 95% CI 1.22-3.86; P = 0.009). Conclusion In a patient cohort under OMT, the adverse prognostic impact of FMR is given predominantly in a sub-cohort of a specific intermediate-failure phenotype-well-defined functionally, haemodynamically, biochemically, and morphologically.

Mitral Leaflet Changes Following Myocardial InfarctionCLINICAL PERSPECTIVE: Clinical Evidence for Maladaptive Valvular Remodeling

Background— Ischemic mitral regurgitation (MR) is classically ascribed to functional restriction of normal leaflets, but recent studies have suggested post–myocardial infarction (MI) mitral valve (MV) leaflet fibrosis and thickening, challenging valve normality. Progression of leaflet thickness post-MI has not been studied. We hypothesized that excessive MV remodeling post-MI contributes to MR. Our objectives are to characterize MV changes after MI and relate them to MR. Methods and Results— Three groups of 40 patients with serial echocardiograms over a mean of 23.4 months were identified from an echocardiography database: patients first studied early (6±12 days) and late (12±7 years) after an inferior MI and normal controls. MV thickness was correlated with MR. We studied the mechanisms for MV changes in a sheep model (6 apical MI versus 6 controls) followed for 8 weeks, with MV cellular and histopathologic analyses. Early post-MI, leaflet thickness was found to be similar to controls (2.6±0.5 vs 2.5±0.4 mm; P=0.23) but significantly increased over time (2.5±0.4 to 2.9±0.4 mm; P<0.01). In this group, patients tolerating maximal doses of renin–angiotensin blocking agents had less thickening (25% of patients; P<0.01). The late-MI group had increased thickness (3.2±0.5 vs 2.5±0.4 mm; P<0.01) without progression. At follow-up, 48% of post-MI patients had more than mild MR. Increased thickness was independently associated with MR. Experimentally, 8 weeks post-MI, MVs were 2-fold thicker than controls, with increased collagen, profibrotic transforming growth factor-&bgr;, and endothelial-to-mesenchymal transformation, confirmed by flow cytometry. Conclusions— MV thickness increases post-MI and correlates with MR, suggesting an organic component to ischemic MR. MV fibrotic remodeling can indicate directions for future therapy.

Evolution of secondary mitral regurgitation

Aims Secondary mitral regurgitation (MR) drives adverse remodelling towards late heart failure stages. Little is known about the evolution of MR under guideline-directed therapy (GDT) and its relation to cardiac remodelling and outcome. We therefore aimed to assess incidence, impact, and predictors of progressive secondary MR in patients under GDT. Methods and results We prospectively enrolled 249 patients with chronic heart failure and reduced ejection fraction receiving GDT in this long-term observational study. Of patients with non-severe MR at baseline 81% remained stable whereas 19% had progressive MR. Those patients were more symptomatic (P < 0.001), had higher neurohumoral activation (encompassing various neurohumoral pathways in heart failure, all P < 0.05), larger left atrial size (P = 0.004) and more tricuspid regurgitation (TR, P = 0.02). During a median follow-up of 61 months (IQR 50-72), 61 patients died. Progression of MR conveyed an increased risk of mortality-univariately (HR 2.33; 95% CI 1.34-4.08; P = 0.003), that persisted after multivariate adjustment using a bootstrap-selected confounder model (adjusted HR 2.48; 95% CI 1.40-4.39; P = 0.002). In contrast, regression of MR was not associated with a beneficiary effect on outcome (crude HR 0.84; 95% CI 0.30-2.30; P = 0.73). Conclusions Every fifth patient with chronic heart failure suffers from MR progression. This entity is associated with a more than two-fold increased risk of death even after careful multivariable adjustment. Symptomatic status, left atrial size, TR, and neurohumoral pathways help to identify patients at risk for progressive secondary MR in an early disease process and open the possibility for closer follow-up and timely intervention.

Refining Long-Term Prediction of Cardiovascular Risk in Diabetes – The VILDIA Score

Cardiovascular risk assessment in patients with diabetes relies on traditional risk factors. However, numerous novel biomarkers have been found to be independent predictors of cardiovascular disease, which might significantly improve risk prediction in diabetic patients. We aimed to improve prediction of cardiovascular risk in diabetic patients by investigating 135 evolving biomarkers. Based on selected biomarkers a clinically applicable prediction algorithm for long-term cardiovascular mortality was designed. We prospectively enrolled 864 diabetic patients of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study with a median follow-up of 9.6 years. Independent risk factors were selected using bootstrapping based on a Cox regression analysis. The following seven variables were selected for the final multivariate model: NT-proBNP, age, male sex, renin, diabetes duration, Lp-PLA2 and 25-OH vitamin D3. The risk score based on the aforementioned variables demonstrated an excellent discriminatory power for 10-year cardiovascular survival with a C-statistic of 0.76 (P < 0.001), which was significantly better than the established UKPDS risk engine (C-statistic = 0.64, P < 0.001). Net reclassification confirmed a significant improvement of individual risk prediction by 22% (95% confidence interval: 14–30%) compared to the UKPDS risk engine (P < 0.001). The VILDIA score based on traditional cardiovascular risk factors and reinforced with novel biomarkers outperforms previous risk algorithms.