Franz Duca

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.

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.

Fluid status and outcome in patients with heart failure and preserved ejection fraction

BACKGROUND Most heart failure with preserved ejection fraction (HFpEF) patients, at some point, present to an emergency department with typical symptoms of volume overload. Clinically, most respond well to standard diuretic therapy, sometimes at the cost of renal function. The study sought to define the prognostic significance of fluid status versus renal function in patients with HFpEF. METHODS One hundred sixty-two consecutive patients with HFpEF were enrolled in our prospective registry. Twelve patients with clinically overt decompensation were excluded. Fluid status at baseline was determined by bioelectrical impedance spectroscopy. The primary outcome measure was a combined end point consisting of hospitalization for heart failure and/or death for cardiac reason. RESULTS Mean age was 74.4±8.4years. Ninety-one (61%) patients were hypo- or normovolemic (relative fluid overload [Rel. FO] -0.7±5.7%) while 59 (39%) patients presented with fluid overload (Rel. FO 11.5±2.7%). During a median follow-up of 24.3months (interquartile range: 19.8-33.2), 34% of patients reached the combined end point. Multivariate Cox hazard analysis identified fluid overload (hazard ratio: 3.09; 95% confidence interval: 1.68-5.68; p<0.001) as an independent predictor of adverse outcome. Patients with fluid overload and normal renal function showed a worse event-free survival compared to the subgroup with normohydration and impaired renal function (log-rank: p=0.042). CONCLUSION HFpEF patients with measurable fluid overload face a dismal prognosis as compared to euvolemic patients. Our data, while preliminary, suggest that patients with fluid overload may face a better outcome under continued fluid removal irrespective of changes in eGFR.

Cardiac extracellular matrix is associated with adverse outcome in patients with chronic heart failure

Accumulation of extracellular matrix (ECM) is known to play a crucial role in the pathophysiology of heart failure (HF). However, its prognostic relevance is poorly investigated.

Presence of ´isolated´ tricuspid regurgitation should prompt the suspicion of heart failure with preserved ejection fraction

Background Diastolic dysfunction of the left ventricle is common but frequently under-diagnosed. Particularly in advanced stages affected patients may present with significant functional tricuspid regurgitation (TR) as the most prominent sign on echocardiography. The underlying left ventricular pathology may eventually be missed and symptoms of heart failure are attributed to TR, with respective therapeutic consequences. The aim of the present study was to determine prevalence and mechanisms underlying TR evolution in heart failure with preserved ejection fraction (HFpEF). Methods and results Consecutive HFpEF patients were enrolled in this prospective, observational study. Confirmatory diagnostic tests including echocardiography and invasive hemodynamic assessments were performed. Of the 175 patients registered between 2010 and 2014, 51% had significant (moderate or severe) TR without structural abnormalities of the tricuspid valve. Significant hemodynamic differences between patients with and without relevant TR were encountered. These included elevated pulmonary vascular resistance (p = 0.038), reduced pulmonary arterial compliance (PAC, p = 0.005), and elevated left ventricular filling pressures (p = 0.039) in the TR group. Multivariable binary logistic regression analysis revealed diastolic pulmonary artery pressure (p = 0.029) and PAC (p = 0.048) as independent determinants of TR. Patients were followed for 18.1±14.1 months, during which 32% had a cardiac event. While TR was associated with outcome in the univariable analysis, it failed to predict event-free survival in the multivariable model. Conclusions The presence of ´isolated´ functional TR should prompt the suspicion of HFpEF. Our data show that significant TR is a marker of advanced HFpEF but neither an isolated entity nor independently associated with event-free survival.