Feature Tracking of Global Longitudinal Strain by Using Cardiovascular MRI Improves Risk Stratification in Heart Failure with Preserved Ejection Fraction.

Background In heart failure with preserved ejection fraction (HFpEF), echocardiographic studies suggest that global longitudinal strain (GLS) has an impact on survival. Feature-tracking cardiovascular MRI also allows for strain analysis; however, to the knowledge of the authors, little is known about its prognostic value and whether it reflects severity of diffuse fibrosis, as assessed by cardiovascular MRI T1 mapping. Purpose To investigate the association between myocardial strain at cardiovascular MRI with extracellular volume by T1 mapping and outcome in participants with HFpEF. Materials and Methods In this secondary analysis of a prospective study (NCT03405987), consecutive participants with HFpEF underwent cardiovascular MRI between July 2012 and March 2018, including T1 mapping and three-dimensional strain analysis. Extracellular volume and strain results were assessed to determine if there was a correlation between these two factors. Cox regression was performed to determine the prognostic relevance of MRI-derived myocardial strain for a combined end point (events) of heart failure hospitalizations and cardiovascular death. Results In total, 206 consecutive participants with HFpEF (mean age, 71 years ± 8 [standard deviation]; 69% women) were included. Median myocardial global longitudinal strain (GLS) at MRI was -8.5% and showed low correlation with extracellular volume (r = 0.28; P = .003). A total of 109 events (53%) were recorded during a follow-up of 38 months ± 29. Participants with a GLS above the median had higher event rates (log-rank test, P < .001). By multivariable Cox regression analysis, GLS remained independently associated with outcome (hazard ratio, 1.06 per 1% strain increase; 95% confidence interval: 1.01, 1.11; P = .03) when corrected for risk factors including age, diabetes, renal function, N-terminal pro-b-type natriuretic peptide serum concentration, and right ventricular size and function. Conclusion In participants with heart failure with preserved ejection fraction, global longitudinal strain at cardiovascular MRI was correlated with extracellular volume by T1 mapping and was associated with cardiovascular events. © RSNA, 2020 Online supplemental material is available for this article.

Persistent atrial fibrillation in heart failure with preserved ejection fraction: Prognostic relevance and association with clinical, imaging and invasive haemodynamic parameters.

BACKGROUND: Atrial fibrillation (AF) is a frequent finding in HFpEF. However, its association with invasive haemodynamics, imaging parameters and outcome in HFpEF is not well established. Furthermore, the relevance of AF subtype with regard to outcome is unclear. This study sought to investigate the prognostic impact of paroxysmal and persistent AF in a well-defined heart failure with preserved ejection fraction (HFpEF) population. MATERIALS AND METHODS: Between 2010 and 2016, 254 HFpEF patients were prospectively enrolled. All patients underwent echocardiography as well as left and right heart catheterization. Patients without contraindications underwent CMR including T1 mapping. Follow-up and outcome data were collected. Patients with significant coronary artery disease were excluded. RESULTS: A total of 153 patients (60%) suffered from AF, 119 (47%) had persistent and 34 (13%) had paroxysmal AF. By multiple logistic regression analysis, persistent AF was independently associated with NT-proBNP (P = .003), NYHA functional class (P = .040), left and right atrial size (P = .022 and <.001, respectively), cardiac output (P = .002) and COPD (P = .034). After a median follow-up of 23 months (interquartile range 5-48), 92 patients (36%) reached the primary end point defined as hospitalization for heart failure or cardiovascular death. By multivariate Cox regression analysis, only persistent AF (P = .005) and six-minute walk distance (P = .011) were independently associated with the primary end point. CONCLUSIONS: Sixty percent of our HFpEF patients suffered from AF. Persistent but not paroxysmal AF was strongly associated with event-free survival and was independently related to NYHA functional class, serum NT-proBNP, atrial size, cardiac ouput and presence of COPD.

Angs (Angiotensins) of the Alternative Renin-Angiotensin System Predict Outcome in Patients With Heart Failure and Preserved Ejection Fraction.

The renin-angiotensin system plays an important role in the development and progression of heart failure (HF). In addition to the classical renin-angiotensin pathway, an alternative pathway produces Angs (angiotensins), which counteract the negative effects of Ang II. We hypothesized that Ang profiling could provide insights into the pathogenesis and prognosis of HF with preserved ejection fraction. We aimed to investigate the effects of Angs on outcome in HF with preserved ejection fraction. Consecutive patients were included into a prospective single-center registry. Clinical, laboratory, and imaging parameters were assessed and serum samples were taken at baseline and measured by mass spectroscopy. Serum equilibrium levels were analyzed in regard to the combined clinical end point of cardiovascular death or HF hospitalization. In total, 155 patients were included during a median follow-up time of 22.5 (interquartile range, 4.0-61.0) months, 52 individuals (34%) reached the combined end point. We identified higher levels of Ang 1-7 and Ang 1-5 as predictors for poor outcome. After adjusting for potential confounding factors, Ang 1-5 remained predictive for poor outcome. In addition to Ang 1-7 and Ang 1-5, the novel ACE (angiotensin-converting enzyme) independent Ang composite marker [Ang 1-7+Ang 1-5] was shown to predict adverse events. We conclude that Angs of the alternative renin-angiotensin system seem to play a role in HF with preserved ejection fraction and are linked to outcome in patients with HF and preserved ejection fraction. Ang 1-5 and the alternative renin-angiotensin system composite marker [Ang 1-7+Ang 1-5] are independent predictors of outcome.

Diagnostic and Prognostic Utility of Cardiac Magnetic Resonance Imaging in Aortic Regurgitation.

OBJECTIVES: This study investigated the diagnostic and prognostic value of cardiac magnetic resonance (CMR) imaging in chronic aortic regurgitation (AR). BACKGROUND: Accurate quantification of AR severity by echocardiography frequently remains difficult. CMR is recommended as the complementary method; however, its accuracy and prognostic utility remain unknown. METHODS: A total of 232 consecutive patients (34.5% were females 55.5 ± 19.8 years of age) with chronic AR (including 40 with moderate to severe and 44 with severe AR on echocardiography) underwent CMR within 4 weeks of echocardiography. CMR included phase-contrast velocity-encoded imaging for the measurement of regurgitant volume and fraction at the sinotubular junction and assessment of holodiastolic retrograde flow (HRF) in the descending aorta. Significant AR was defined as the presence of HRF on CMR. Patients were followed prospectively, and multivariate Cox regression was applied for outcome analysis using a combination of heart failure, hospitalization, and cardiovascular death as primary endpoint. RESULTS: AR severity on the basis of echo was reclassified in a significant number of patients according to CMR: 6.8% with mild AR on echo had HRF on CMR, whereas 34.1% with severe AR on echo did not have HRF on CMR and were reclassified as having nonsignificant AR. In 40 patients with uncertain AR severity (moderate to severe) on echo, 45.0% had HRF on CMR, indicating severe AR. Patients were followed for 35.3 ± 26.6 months. During that period, 63 patients (27.2%) reached the combined endpoint, including 43 (18.5%) with heart failure hospitalizations and 20 (8.6%) with cardiovascular deaths. By multivariate regression analysis, including clinical as well as imaging parameters, only N-terminal pro-B-type natriuretic peptide concentration (hazard ratio: 2.184 [95% confidence interval: 1.468 to 3.248]; p < 0.001) and HRF on CMR (hazard ratio: 2.774 [95% confidence interval: 1.131 to 6.802]; p = 0.026) remained significantly associated with outcome. CONCLUSIONS: In chronic AR, CMR has the potential to add important diagnostic and prognostic information.

Gender-related differences in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) affects more women than men, suggesting gender to play a major role in disease evolution. However, studies investigating gender differences in HFpEF are limited. In the present study we aimed to describe gender differences in a well-characterized HFpEF cohort. Consecutive HFpEF patients underwent invasive hemodynamic assessment, cardiac magnetic resonance imaging and exercise testing. Study endpoints were: cardiac death, a combined endpoint of HF hospitalization or cardiac death and all-cause death. 260 HFpEF patients were prospectively enrolled. Men were more compromised with regard to exercise capacity and had significantly more co-morbidities. Men had more pronounced pulmonary vascular disease with higher diastolic pressure gradients and a lower right ventricular EF. During follow-up, 9.2% experienced cardiac death, 33.5% the combined endpoint and 17.3% all-cause death. Male gender was independently associated with cardiac death, but neither with the combined endpoint nor with all-cause mortality. We detected clear gender differences in HFpEF patients. Cardiac death was more common among men, but not all-cause death. While men are more prone to develop a right heart phenotype and die from HFpEF, women are more likely to die with HFpEF.

Extracellular volume quantification by cardiac magnetic resonance imaging without hematocrit sampling : Ready for prime time?

BACKGROUND: Myocardial tissue characterization by cardiovascular magnetic resonance (CMR) T1 mapping currently receives increasing interest as a diagnostic tool in various disease settings. The T1-mapping technique allows non-invasive estimation of myocardial extracellular volume (ECV) using T1-times before and after gadolinium administration; however, for calculation of the myocardial ECV the hematocrit is needed, which limits its utility in routine application. Recently, the alternative use of the blood pool T1-time instead of the hematocrit has been described. METHODS: The results of CMR T1 mapping data of 513 consecutive patients were analyzed for this study. Blood for hematocrit measurement was drawn when placing the i. v. line for contrast agent administration. Data from the first 200 consecutive patients (derivation cohort) were used to establish a regression formula allowing synthetic hematocrit calculation, which was then validated in the following 313 patients (validation cohort). Synthetic ECV was calculated using synthetic hematocrit, and was compared with conventionally derived ECV. RESULTS: Among the entire cohort of 513 patients (mean age 57.4 ± 17.5 years old, 49.1% female) conventionally measured hematocrit was 39.9 ± 4.7% and native blood pool T1-time was 1570.6 ± 117.8 ms. Hematocrit and relaxivity of blood (R1 = 1/blood pool T1 time) were significantly correlated (r = 0.533, r2 = 0.284, p < 0.001). By linear regression analysis, the following formula was developed from the derivation cohort: synthetic hematocrit = 628.5 × R1 - 0.002. Synthetic and conventional hematocrit as well as ECV showed significant correlation in the validation (r = 0.533, r2 = 0.284, p < 0.001 and r = 0.943, r2 = 0.889, p < 0.001, respectively) as well as the overall cohort (r = 0.552, r2 = 0.305, p < 0.001 and r = 0.957, r2 = 0,916, p < 0.001). By Bland Altman analysis, good agreement between conventional and synthetic ECV was found in the validation cohort (mean difference: 0.007%, limits of agreement: -4.32 and 4.33%, respectively). CONCLUSION: Synthetic ECV using native blood pool T1-times to calculate the hematocrit, is feasible and leads to almost identical results in comparison with the conventional method. It may allow fully automatic ECV-mapping and thus enable broader use of ECV by CMR T1 mapping in clinical practice.

Wedge Pressure Rather Than Left Ventricular End-Diastolic Pressure Predicts Outcome in Heart Failure With Preserved Ejection Fraction.

OBJECTIVES: This study sought to compare the prognostic power of left ventricular end-diastolic pressure (LVEDP) and pulmonary arterial wedge pressure (PAWP) in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: It is broadly accepted that direct measurement of LVEDP in HFpEF more robustly reflects left ventricular hemodynamics than PAWP. METHODS: A total of 173 consecutive HFpEF patients were prospectively enrolled. Of these, 152 patients fulfilled registry inclusion criteria. Study participants underwent clinical evaluation, lung function tests, echocardiography, cardiac magnetic resonance, coronary angiography, and invasive hemodynamic assessments with PAWP and LVEDP measurements in 1 procedure. The study endpoint was defined as hospitalization for heart failure or cardiac death. RESULTS: A modest pressure difference (2.0 ± 4.4 mm Hg) was observed between PAWP (21.5 ± 5.6 mm Hg) and LVEDP (19.5 ± 5.2 mm Hg) at baseline. After a mean follow-up of 23.5 ± 21.3 months, PAWP was predictive of outcome (p = 0.010), whereas LVEDP was not (p = 0.261) by Kaplan-Meier curves. By multivariate regression analysis, diffusion capacity of carbon monoxide (DLCO) was the only parameter that was independently related to the pressure difference between PAWP and LVEDP. When patients were stratified according to DLCO between ≤45% and >45%, those in the low DLCO group were found to have a more pronounced pressure drop between PAWP and LVEDP (3.1 ± 4.8 mm Hg vs. 0.8 ± 3.8 mm Hg, respectively; p = 0.031) and to be in more advanced disease stages. CONCLUSIONS: Our data indicate that PAWP but not LVEDP is associated with outcome in HFpEF. A more pronounced difference between PAWP and LVEDP and more advanced disease is found in patients with low DLCO.

Diameter of the Pulmonary Artery in Relation to the Ascending Aorta: Association with Cardiovascular Outcome.

Purpose To investigate whether the pulmonary artery (PA)-to-ascending aorta (Ao) ratio is associated with outcome in unselected patients referred for cardiac magnetic resonance (MR) imaging. Materials and Methods This study prospectively enrolled 650 consecutive patients (47.2% women; mean age, 56.1 years ± 17.7 [standard deviation]). Diameters of PA and Ao were measured in axial black blood images. On the basis of previous results, a PA-to-Ao ratio of 1.0 or greater was chosen as the cutoff for further analysis. Univariable and multivariable Cox regression models were used to investigate the primary end point, which was defined as a composite of cardiovascular hospitalization and death. Results A PA-to-Ao ratio of 1.0 or greater was present in 131 (20.2%) patients. Patients with a PA-to-Ao ratio of 1.0 or greater were predominantly women (P = .010); more frequently presented with atrial fibrillation (P < .001), diabetes (P < .001), and impaired renal function (P < .001); and had higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (P < .001), larger left (P = .023) and right ventricles (RV; P = .002), and worse RV function (P < .001). Patients were followed for 17.8 months ± 12.9, during which 110 patients (16.9%) reached the primary end point. By Kaplan-Meier analysis, event-free survival was significantly worse in patients with a PA-to-Ao ratio of 1.0 or greater (log-rank test, P < .001). A PA-to-Ao ratio of 1.0 or greater was independently associated with outcome by multivariable Cox regression analysis, in addition to age, NT-proBNP serum levels, and RV size. Conclusion A PA-to-Ao ratio of 1.0 or greater identified patients at risk, most likely because of elevated PA pressures. On the basis of these results, the PA-to-Ao ratio should routinely be reported at cardiac MR imaging. © RSNA, 2017 Online supplemental material is available for this article.

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.

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.

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.

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

AIMS: 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. METHODS AND RESULTS: A total of 73 HF patients who underwent LV endomyocardial biopsy were enrolled in our study. ECM area was quantified by TissueFAXS and ImageJ software. Patients were followed-up at 6-month intervals. The study endpoint was defined as hospitalization for a cardiac reason and/or cardiac death. Furthermore, the influence of the ECM on invasively measured haemodynamic parameters was tested. During a median follow-up period of 9.0 months, 34 patients (46.6%) reached the combined endpoint. Median ECM area was 30.5%. Patients with ECM area ≥30.5% experienced significantly more events (67.6% vs. 25.0%, P < 0.001) in comparison with patients with an ECM area <30.5%. ECM area was independently associated with outcome in the total HF cohort [hazard ratio (HR) 1.041, 95% confidence interval (CI) 1.017-1.066, P = 0.001] as well as in HF patients with preserved (HR 1.079, 95% CI 1.001-1.163, P =0 .046) or reduced ejection fraction (HR 1.149, 95% CI 1.036-1.275, P = 0.009). Positive correlations were found between ECM area and LV end-diastolic pressure (P = 0.021, R = 0.303), pulmonary artery wedge pressure (P = 0.042, R = 0.249), mean pulmonary arterial pressure (P = 0.035, R = 0.258), as well as right atrial pressure (P = 0.003, R = 0.353). CONCLUSION: ECM area within the LV myocardium correlates with left and right heart haemodynamics and is associated with clinical course in various non-ischaemic HF types.

Interstitial Fibrosis, Functional Status, and Outcomes in Heart Failure With Preserved Ejection Fraction: 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.

Riociguat for the treatment of pulmonary hypertension: a safety evaluation.

INTRODUCTION: The development of pulmonary hypertension (PH) has multifactorial underlying pathophysiological causes and can be classified into five groups. While three different classes of therapeutic drugs are licensed for the treatment of pulmonary arterial hypertension (PAH, WHO group 1), specific medical therapies are lacking for other forms of PH, such as PH due to left heart disease. In 2013 riociguat, a first-in class soluble guanylate cyclase stimulator, has also become available for the treatment of PAH. Riociguat was further introduced as the first approved pharmacotherapy for the treatment of patients with chronic thromboembolic PH (WHO group 4, CTEPH). Despite these advances in therapeutic options for patients with PH, none of these agents have been approved for the treatment of PH due to left heart disease. Areas covered: We aim to give an overview of the pathophysiology of PH, pharmacodynamics and pharmacokinetic properties, safety and efficacy of riociguat, including adverse events, contraindications and drug interactions. Expert opinion: Considering the increasingly broad indications for riociguat in patients with PH, substantial knowledge of data and properties on safety and efficacy of riociguat are becoming more and more important for physicians prescribing riociguat to PH patients.

Functional Status, Pulmonary Artery Pressure, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Patients with heart failure with preserved ejection fraction have functional impairment resulting in reduced quality of life. Specific pathological mechanisms underlying symptoms have not yet been defined. OBJECTIVES: The aim of this study was to identify hemodynamic and other patient-related variables that are associated with New York Heart Association (NYHA) functional class and to analyze functional class in perspective with other clinical, laboratory, imaging, and hemodynamic parameters with respect to its influence on outcomes. METHODS: Between January 2011 and February 2015, 193 patients with confirmed heart failure with preserved ejection fraction were enrolled. RESULTS: Those in more advanced NYHA functional classes (III and IV; n = 136) were older (p = 0.008), had higher body mass indexes (p = 0.004), and had higher levels of N-terminal pro-brain natriuretic peptide (p = 0.001) compared with less symptomatic patients (NYHA class II; n = 57). Furthermore, parameters reflecting left ventricular diastolic dysfunction were more pronounced in advanced NYHA classes (early mitral inflow velocity/early diastolic mitral annular velocity; p = 0.023) as well as parameters reflecting right ventricular afterload (diastolic pulmonary artery pressure; p < 0.001). By multivariate regression analysis, age (p = 0.007), body mass index (p = 0.002), N-terminal pro-brain natriuretic peptide (p < 0.001), early mitral inflow velocity/mitral peak velocity of late filling (p = 0.031), and diastolic pulmonary artery pressure (p < 0.001) were independently associated with advanced NYHA class. After 21.9 months of follow-up, 64 patients (33.2%) reached the combined endpoint, defined as hospitalization for heart failure and/or cardiac death. By multivariate Cox analysis, NYHA functional class was independently associated with outcome (hazard ratio: 2.133; p = 0.040), as well as N-terminal pro-brain natriuretic peptide (hazard ratio: 1.655; p < 0.001) and impaired right ventricular function (hazard ratio: 2.360; p = 0.001). CONCLUSIONS: Symptoms of breathlessness in patients with heart failure with preserved ejection fraction are multifactorial and largely related to body mass index, left ventricular diastolic function, and the pulmonary vasculature. Clinically meaningful therapeutic interventions should target body weight, left ventricular stiffness, and concomitant pulmonary vascular disease.

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

AIMS: 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. METHODS AND RESULTS: We prospectively included 144 consecutive patients with HFpEF in our observational, non-interventional registry. Echocardiography, CMR imaging, and invasive haemodynamic assessments including myocardial biopsy were performed at baseline. We did not observe a significant association between soluble neprilysin levels and hospitalization for heart failure and/or death in the Cox regression analysis (P = 0.56). Furthermore, there were no significant differences between tertiles of neprilysin in outcome, functional markers, established risk factors for HFpEF, CMR measurements including post-contrast T1 time, extracellular matrix obtained by myocardial biopsy, and invasive haemodynamic measurements. NT-proBNP demonstrated a weak correlation with levels of soluble neprilysin (r = - 0.26, P = 0.002). CONCLUSION: Our results describe for the first time circulating levels of soluble neprilysin in patients with HFpEF. In contrast to HFrEF, we could not confirm an association between neprilysin levels and cardiovascular mortality or hospitalization for heart failure.

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.