Andreas A. Kammerlander

Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size

RATIONALE Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes. OBJECTIVE The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST-segment resolution, and infarct size. METHODS AND RESULTS We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo. CONCLUSIONS PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size.

T1 Mapping by CMR Imaging: From Histological Validation to Clinical Implication

OBJECTIVES The purpose of this study was to prospectively investigate the diagnostic and prognostic impact of cardiac magnetic resonance (CMR) T1 mapping and validate it against left ventricular biopsies. BACKGROUND Extracellular volume (ECV) expansion is a key feature of heart failure. CMR T1 mapping has been developed as a noninvasive technique to estimate ECV; however, the diagnostic and prognostic impacts of this technique have not been well established. METHODS A total of 473 consecutive patients referred for CMR (49.5% female, age 57.8 ± 17.1 years) without hypertrophic cardiomyopathy, cardiac amyloidosis, or Anderson-Fabry disease were studied. T1 mapping with the modified Look-Locker inversion recovery (MOLLI) sequence was used for ECV calculation (CMR-ECV). For methodological validation, 36 patients also underwent left ventricular biopsy, and ECV was quantified by TissueFAXS analysis (TissueFAXS-ECV). To assess the prognostic value of CMR-ECV, its association with hospitalization for cardiovascular reasons or cardiac death was tested in a multivariable Cox regression model. RESULTS TissueFAXS-ECV was 26.3 ± 7.2% and was significantly correlated with CMR-ECV (r = 0.493, p = 0.002). Patients were followed up for 13.3 ± 9.0 months and divided into CMR-ECV tertiles for Kaplan-Meier analysis (tertiles were ≤ 25.7%, 25.8% to 28.5%, and ≥ 28.6%). Significantly higher event rates were observed in patients with higher CMR-ECV (log-rank p = 0.013). By multivariable Cox regression analysis, CMR-ECV was independently associated with outcome among imaging variables (p = 0.004) but not after adjustment for clinical parameters. CONCLUSIONS CMR T1 mapping allows accurate noninvasive quantification of ECV and is independently associated with event-free survival among imaging parameters. Its prognostic value on top of established clinical risk factors warrants further investigation in long-term studies.

The right heart in heart failure with preserved ejection fraction: insights from cardiac magnetic resonance imaging and invasive haemodynamics.

Recent data indicate that right ventricular systolic dysfunction (RVSD) by cardiac magnetic resonance imaging (CMR) is a strong predictor of outcome in heart failure. However, the prognostic significance of RVSD by CMR in heart failure with preserved ejection fraction (HFpEF) is unknown.

Interstitial Fibrosis, Functional Status, and Outcomes in Heart Failure With Preserved Ejection FractionCLINICAL PERSPECTIVE: Insights From a Prospective Cardiac Magnetic Resonance Imaging Study

Background—Myocardial extracellular volume (ECV) accumulation is one of the key pathophysiologic features of heart failure with preserved ejection fraction (HFpEF). Our aims were to (1) measure ECV by cardiac magnetic resonance T1 mapping using the modified Look-Locker inversion recovery (MOLLI) sequence, (2) validate MOLLI-ECV against histology, and (3) investigate the relationship between MOLLI-ECV and prognosis in HFpEF. Methods and Results—One-hundred seventeen consecutive HFpEF patients underwent cardiac magnetic resonance imaging, coronary angiography, and invasive hemodynamic assessments at baseline. Eighteen patients also underwent left ventricular biopsy for histological analysis (Histo-ECV). To assess the prognostic impact of MOLLI-ECV, its association with hospitalization for heart failure/cardiac death was tested by multivariable Cox regression analysis. Histo-ECV was 30.1±4.6% and was significantly correlated with MOLLI-ECV (R=0.494, P=0.037). Patients were followed for 24.0 months (6.0–32.0 months), during which 34 had a cardiac event. By Kaplan–Meier analysis, patients with MOLLI-ECV ≥ the median (28.9%) had shorter event-free survival (log-rank, P=0.028). MOLLI-ECV significantly correlated with N-terminal prohormone of brain natriuretic peptide (P<0.001), 6-minute walk distance (P=0.004), New York Heart Association functional class (P=0.009), right atrial pressure (P=0.037), and stroke volume (P=0.043). By multivariable Cox regression analysis, MOLLI-ECV was associated with outcome among imaging variables (P=0.038) but not after adjustment for clinical and invasive hemodynamic parameters. Conclusions—We demonstrate that MOLLI-ECV in HFpEF accurately reflects histological ECV, correlates with markers of disease severity, and is associated with outcome among cardiac magnetic resonance parameters but not after adjustment for important clinical and invasive hemodynamic parameters. Nevertheless, MOLLI-ECV has the potential of becoming an important biomarker in HFpEF.

Diastolic Pressure Gradient Predicts Outcome in Patients With Heart Failure and Preserved Ejection Fraction.

Approximately 50% of patients presenting with clinical signs of heart failure are diagnosed with heart failure with preserved ejection fraction (HFpEF) [(1)][1]. Pulmonary hypertension (PH) is a common feature of HFpEF and predicts poor outcome. According to the diastolic pressure gradient (DPG),

Outcome in Heart Failure with Preserved Ejection Fraction: The Role of Myocardial Structure and Right Ventricular Performance

Background Heart failure with preserved ejection fraction (HFpEF) is recognized as a major cause of cardiovascular morbidity and mortality. Thus, a profound understanding of the pathophysiologic changes in HFpEF is needed to identify risk factors and potential treatment targets in this specific patient population. Therefore, we aimed to comprehensively assess the impact of left- and right-ventricular function and hemodynamics on long-term mortality and morbidity in order to improve risk prediction in patients with HFpEF. Methods and Results We prospectively included 142 consecutive patients with HFpEF into our observational, non-interventional registry. Echocardiography, cardiac magnetic resonance imaging and invasive hemodynamic assessments including myocardial biopsy were performed at baseline. We detected significant correlations between left ventricular extracellular matrix and left ventricular end-diastolic diameter (r = -0.64;p = 0.03) and stroke volume (r = -0.53;p = 0.04). Hospitalization for heart failure and/or cardiac death was observed over a median follow up of 10 months. The strongest risk factors were reduced right ventricular function (adj. HR 6.62;95%CI 3.12- 14.02;p<0.001), systolic pulmonary arterial pressure (adj. HR per 1-SD 1.55;95%CI 1.15- 2.09;p = 0.004) and the pulmonary artery wedge pressure (adj. HR per 1-SD 1.51;95%CI 1.09–2.08; p = 0.012). The area under the ROC curve for right ventricular function was 0.63, for systolic pulmonary arterial pressure 0.75, and for pulmonary artery wedge pressure 0.68. Conclusion The current study emphasizes the importance of right ventricular function and pulmonary pressures on outcome in patients with HFpEF providing pathophysiological insights into the hemodynamic changes in HFpEF.

Soluble neprilysin does not correlate with outcome in heart failure with preserved ejection fraction

Circulating soluble neprilysin, an endopeptidase that catalyses the degradation of various endogenous vasodilators, predicts outcome in patients with heart failure and reduced ejection fraction (HFrEF). In the present study, we measured for the first time circulating soluble neprilysin in a prospective cohort of patients with heart failure with preserved ejection fraction (HFpEF) and correlated the serum levels to outcome, functional markers, established risk factors for HFpEF, myocardial fibrosis assessed by cardiac magnetic resonance (CMR) imaging, as well as histological data obtained by myocardial biopsy and various invasive haemodynamic measurements.

Factors determining patient-prosthesis mismatch after aortic valve replacement--a prospective cohort study.

Objective “Patient-prosthesis mismatch” (PPM) after aortic valve replacement (AVR) has been reported to increase morbidity and mortality. Although algorithms have been developed to avoid PPM, factors favouring its occurrence have not been well defined. Design and Setting This was a prospective cohort study performed at the Medical University of Vienna. Patients 361 consecutive patients who underwent aortic valve replacement for isolated severe aortic stenosis were enrolled. Main Outcome Measures Patient- as well as prosthesis-related factors determining the occurrence of moderate and severe PPM (defined as effective orifice area indexed to body surface area ≤ 0.8 cm2/m2) were studied. Results Postoperatively, 172 patients (48%) were diagnosed with PPM. The fact that predominantly female patients were affected (58% with PPM diagnosis in women versus 36% in men, p<0.001) was explained by the finding that they had smaller aortic root diameters (30.5±4.7 mm versus 35.3±4.2 mm, p<0.0001) and a higher proportion of bioprosthetic valves (82% versus 62%, p<0.0001), both independent predictors of PPM (aortic root diameter: OR 0.009 [95% CI, 0.004;0.013]; p = 0.0003, presence of bioprosthetic valve: OR 0.126 [95% CI, 0.078;0.175]; p<0.0001). Conclusions The occurrence of PPM is determined by aortic root diameter and prosthesis type. Novel sutureless bioprostheses with optimized hemodynamic performance or transcatheter aortic valves may become a promising alternative to conventional bioprosthetic valves in the future.

Modes of death in patients with heart failure and preserved ejection fraction

BACKGROUND Recent studies suggest that reduced right ventricular function is an important predictor of outcome in patients with heart failure and preserved ejection fraction (HFpEF). Because affected patients suffer from a broad spectrum of non-cardiac co-morbidities, it remains unclear, whether they actually die from right heart failure (RHF) or as a consequence of other conditions. METHODS Consecutive patients with a confirmed diagnosis of HFpEF were enrolled in this prospective registry. Local and external medical records, as well as telephone interviews with relatives were used to ascertain modes of death. RHF was accepted as a mode of death, if the following criteria were met: 1. right ventricular dysfunction assessed by transthoracic echocardiography, and 2. clinical signs of right heart decompensation at the time of death. RESULTS Out of 230 patients with complete follow-up, 16.5% (n=38) died after a mean of 30±17months. 60.5% deaths were classified as cardiovascular and 34.2% as non-cardiovascular. In 5.3% patients, the reason for death remained unknown. Of the cardiovascular cases (n=23), 91.4% of deaths were attributed to RHF, 4.3% died from stroke and 4.3% from sudden cardiac death. Of the non-cardiovascular deaths (n=13), 46.2% of deaths were attributed to major infections and 38.4% deaths were related to cancer. Other reasons for death included ileus (7.7%) and major bleeding (7.7%). CONCLUSION In our well-characterised HFpEF cohort, more than half of all deaths could directly be attributed to RHF. The right ventricle seems to be a meaningful therapeutic target in a subset of patients.

Prognostic Impact of Tricuspid Regurgitation in Patients Undergoing Aortic Valve Surgery for Aortic Stenosis

Background The prognostic significance of tricuspid regurgitation (TR) and right ventricular (RV) function in patients undergoing aortic valve replacement (AVR) for severe aortic stenosis (AS) is unknown. The aim of the present study was to evaluate the impact of TR and RV systolic dysfunction on early and late mortality in this setting. Methods This was a prospective single-center observational study. 465 consecutive patients who were referred to AVR for severe AS were investigated. Significant TR was defined as TR≥moderate by transthoracic echocardiography. Results At baseline, significant TR was present in 26 (5.6%) patients. Patients with TR presented with a higher EuroSCORE I (p = 0.001), a higher incidence of previous cardiac surgery (p<0.001), pulmonary hypertension (p = 0.003), more dilated RVs (p = 0.001), and more frequent RV dysfunction (p = 0.001). Patients were followed for an average of 5.2 (±2.8 SD) years. By multivariable Cox regression analysis TR (p = 0.014), RV dysfunction (p = 0.046), age (p = 0.001) and concomitant coronary artery bypass graft surgery (CABG, p = 0.003) were independently associated with overall mortality. By Kaplan-Meier analysis, survival rates were significantly worse in patients with significant than with non-significant TR (log rank p = 0.001). Conclusions TR, RV dysfunction, age, and concomitant CABG are associated with outcome in patients undergoing AVR for severe AS. This finding underlines the importance of a thorough echocardiographic evaluation with particular consideration of the right heart in these patients.