Effect of vericiguat on left ventricular structure and function in patients with heart failure with reduced ejection fraction: The VICTORIA echocardiographic substudy.

AIM: Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodelling with vericiguat in patients with HF with reduced ejection fraction (HFrEF). The aim of this study was to compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF. METHODS AND RESULTS: Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co-primary endpoints were changes in LV end-systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading were performed by an echocardiographic core laboratory blinded to treatment assignment. A total of 419 patients (208 vericiguat, 211 placebo) with high-quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7 ± 26.8 to 56.8 ± 30.4 ml/m2 ; p < 0.01) and LVEF significantly increased (33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI -3.8 ± 15.4 vs. -7.1 ± 20.5 ml/m2 ; p = 0.07 and LVEF +3.2 ± 8.0% vs. +2.4 ± 7.6%; p = 0.31). The absolute rate per 100 patient-years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8) than the placebo group (29.6) (p = 0.07). CONCLUSIONS: In this pre-specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high-risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat's benefit in HFrEF.

Peak O2 -pulse predicts exercise training-induced changes in peak V̇O2 in heart failure with preserved ejection fraction.

AIMS: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O2 ) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter-individual responses vary significantly. Because it is unlikely that ET-induced improvements in peak V̇O2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O2 -pulse (V̇O2  × HR-1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O2 , is inversely associated with the change in peak V̇O2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF. METHODS AND RESULTS: This was a secondary analysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇O2 (%) was analysed as a function of baseline peak V̇O2 and its determinants (absolute peak V̇O2 , peak O2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O2 through changes in peak O2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O2 -pulse explained approximately 72% of the difference in changes in peak V̇O2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O2 -pulse on change in peak V̇O2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O2 -pulse was associated with a decreased mean change in peak V̇O2 of -1.45% (95% CI, -2.30 to -0.60, P = 0.001) compared with a mean change of -0.08% (95% CI, -1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O2 (P > 0.05). Change in V̇O2 at VT1 was not associated with any of the investigated factors (P > 0.05). CONCLUSIONS: In patients with HFpEF, the easily measurable peak O2 -pulse seems to be a good indicator of the potential for improving peak V̇O2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O2 -pulse, patients with high O2 -pulse may need to use additional therapies to significantly increase peak V̇O2 .

The non-invasive assessment of myocardial work by pressure-strain analysis: clinical applications.

Pressure-volume (PV) analysis is the most comprehensive way to describe cardiac function, giving insights into cardiac mechanics and energetics. However, PV analysis still remains a highly invasive and time-consuming method, preventing it from integration into clinical practice. Most of the echocardiographic parameters currently used in the clinical routine to characterize left ventricular (LV) systolic function, such as LV ejection fraction and LV global longitudinal strain, do not take the pressure developed within the LV into account and therefore fall too short in describing LV function as a hydraulic pump. Recently, LV pressure-strain analysis has been introduced as a new technique to assess myocardial work in a non-invasive fashion. This new method showed new insights in comparison to invasive measurements and was validated in different cardiac pathologies, e.g., for the detection of coronary artery disease, cardiac resynchronization therapy (CRT)-response prediction, and different forms of heart failure. Non-invasively assessed myocardial work may play a major role in guiding therapies and estimating prognosis. However, its incremental prognostic validity in comparison to common echocardiographic parameters remains unclear. This review aims to provide an overview of pressure-strain analysis, including its current application in the clinical arena, as well as potential fields of exploitation.

Multimodality imaging in patients with heart failure and preserved ejection fraction: an expert consensus document of the European Association of Cardiovascular Imaging.

Nearly half of all patients with heart failure (HF) have a normal left ventricular (LV) ejection fraction (EF) and the condition is termed heart failure with preserved ejection fraction (HFpEF). It is assumed that in these patients HF is due primarily to LV diastolic dysfunction. The prognosis in HFpEF is almost as severe as in HF with reduced EF (HFrEF). In contrast to HFrEF where drugs and devices are proven to reduce mortality, in HFpEF there has been limited therapy available with documented effects on prognosis. This may reflect that HFpEF encompasses a wide range of different pathological processes, which multimodality imaging is well placed to differentiate. Progress in developing therapies for HFpEF has been hampered by a lack of uniform diagnostic criteria. The present expert consensus document from the European Association of Cardiovascular Imaging (EACVI) provides recommendations regarding how to determine elevated LV filling pressure in the setting of suspected HFpEF and how to use multimodality imaging to determine specific aetiologies in patients with HFpEF.

Relation of left atrial function with exercise capacity and muscle endurance in patients with heart failure.

AIMS: Both left atrial strain (LAS) and skeletal muscle endurance demonstrate a linear relationship to peak VO2 . Less is known about the relationship between central (cardiac) and peripheral (muscle endurance) limitations of exercise capacity in patients with heart failure (HF). We investigated this relationship using novel cardiac markers such as LAS and left atrial emptying fraction (LAEF). METHODS AND RESULTS: We analysed echocardiographic measurements, cardiopulmonary exercise testing (CPET), and isokinetic muscle function in 55 subjects with HF and controls [17 heart failure with preserved ejection fraction (HFpEF), 18 heart failure with reduced ejection fraction (HFrEF), and 20 healthy controls]. Patients with reduced LAEF showed reduced peak VO2 : 14.3 ± 3.5 vs. 18.5 ± 3.5 mL/min/kg, P = 0.003, and reduced muscle endurance (RME): 64.3 ± 23.9 vs. 88.5 ± 32.3 Nm/kg, P = 0.028. Patients with reduced LAS showed similar results. Neither left ventricular global longitudinal strain (LVGLS) nor left atrial volume index (LAVI) was associated with RME. The area under the curve of LAS and LAEF in patients with HF in association with RME were (0.76 vs. 0.80) with 95% confidence interval (CI) (0.59-0.96, P = 0.012 vs. 0.63-0.98, P = 0.006, respectively). In a multiple linear regression, LAEF and working load measured during CPET (watt) were independent factors for RME after adjusting for age, LVGLS, and 6 min walk test (6MWT) [LAEF (B: 0.09, 95% CI: 1.01; 1.18, P = 0.024), working load (B: 0.05, 95% CI: 1.01; 1.08, P = 0.006)]. Peak torque of the left leg was associated with E/LAS (E: early diastolic) in patients with HFpEF (r = -0.6, P = 0.020). Endurance of the left leg was associated with LAEF (r = 0.79, P = 0.001) in patients with HFrEF. CONCLUSIONS: LAS/LAEF are potential cardiac markers in demonstrating the link between cardiac and peripheral limitations of exercise capacity. Thus, integrating LAS/LAEF in the evaluation of exercise intolerance in patients with HF could be useful.

Left atrial diverticulum-An unexpected finding in routine transesophageal echocardiography.

We report a 55-year-old male patient with lone paroxysmal atrial fibrillation who underwent routine transesophageal echocardiography (TOE) at our institution. In a mid-esophageal 125° three-chamber angulation, a distinct thinning of the left atrial (LA) wall was observed, forming a 7 × 4 mm canal with only a small membrane separating the LA from the pericardial space. Cardiac magnetic resonance imaging diagnosed a small LA diverticulum. To the best of our knowledge, this is the first manuscript describing detection of a small LA diverticulum via TOE.

Left atrial strain as sensitive marker of left ventricular diastolic dysfunction in heart failure.

AIMS: The purpose of this retrospective analysis was to examine the association of left atrial (LA) strain (i.e. LA reservoir function) with left ventricular diastolic dysfunction (DD) in patients with heart failure with reduced and preserved left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We analysed the baseline echocardiographic recordings of 300 patients in sinus rhythm from the SOCRATES-PRESERVED and SOCRATES-REDUCED studies. LA volume index was normal in 89 (29.7%), of whom 60.6% had an abnormal LA reservoir strain (i.e. ≤23%). In addition, the extent of LA strain impairment was significantly associated with the severity of DD according to the 2016 American Society of Echocardiography recommendations (DD grade I: LA strain 22.2 ± 6.6, rate of abnormal LA strain 62.9%; DD grade II: LA strain 16.6 ± 7.4, rate of abnormal LA strain 88.6%; DD grade III: LA strain 11.1 ± 5.4%, rate of abnormal LA strain 95.7%; all P < 0.01). In line with these findings, LA strain had a good diagnostic performance to determine severe DD [area under the curve 0.83 (95% CI 0.77-0.88), cut-off 14.1%, sensitivity 80%, specificity 77.8%], which was significantly better than for LA volume index, LA total emptying fraction, and the mitral E/e' ratio. CONCLUSIONS: The findings of this analysis suggest that LA strain could be a useful parameter in the evaluation of DD in patients with heart failure and sinus rhythm, irrespective of LVEF.

How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the 'HFA-PEFF diagnostic algorithm'. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory setting and includes assessment for heart failure symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular (LV) ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e'), LV filling pressure estimated using E/e', left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2-4 points) implies diagnostic uncertainty, in which case Step 3 (F1 : Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2 : Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.

Potential usefulness and clinical relevance of a novel left atrial filling index to estimate left ventricular filling pressures in patients with preserved left ventricular ejection fraction.

AIMS: The aim of this study was to examine the potential usefulness and clinical relevance of a novel left atrial (LA) filling index using 2D speckle-tracking transthoracic echocardiography to estimate left ventricular (LV) filling pressures in patients with preserved LV ejection fraction (LVEF). METHODS AND RESULTS: The LA filling index was calculated as the ratio of the mitral early-diastolic inflow peak velocity (E) over LA reservoir strain (i.e. E/LA strain ratio). This index showed a good diagnostic performance to determine elevated LV filling pressures in a test-cohort (n = 31) using invasive measurements of LV end-diastolic pressure (area under the curve 0.82, cut-off > 3.27 = sensitivity 83.3%, specificity 78.9%), which was confirmed in a validation-cohort (patients with cardiovascular risk factors; n = 486) using the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging criteria (cut-off > 3.27 = sensitivity 88.1%, specificity 77.6%) and in a specificity-validation cohort (patients free of cardiovascular risk factors, n = 120; cut-off > 3.27 = specificity 98.3%). Regarding the clinical relevance of the LA filling index, an elevated E/LA strain ratio (>3.27) was significantly associated with the risk of heart failure hospitalization at 2 years (odds ratio 4.3, 95% confidence interval 1.8-10.5), even adjusting this analysis by age, sex, renal failure, LV hypertrophy, or abnormal LV global longitudinal systolic strain. CONCLUSION: The findings from this study suggest that a novel LA filling index using 2D speckle-tracking echocardiography could be of potential usefulness and clinical relevance in estimating LV filling pressures in patients with preserved LVEF.

How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the 'HFA-PEFF diagnostic algorithm'. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory setting and includes assessment for HF symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e'), left ventricular (LV) filling pressure estimated using E/e', left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2-4 points) implies diagnostic uncertainty, in which case Step 3 (F1: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2: Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.

Phasic Left Atrial Function in Cancer Patients Before Initiation of Anti-Cancer Therapy.

: We aimed to explore left atrial (LA) remodeling in the patients with solid cancer before initiation of chemo- or radiotherapy. This retrospective investigation included 92 chemo- and radiotherapy-naive cancer patients and 40 age- and gender-matched controls with a similar cardiovascular risk profile as the cancer group. All participants underwent comprehensive echocardiographic examination before the start of chemo- or radiotherapy. LA phasic function was evaluated in volumetric and strain method. Indexed minimal and pre-A LA volumes were significantly higher in the cancer patients. Total and passive LA emptying fraction (EF) were significantly lower, whereas active LAEF was significantly higher in the cancer patients. LA total longitudinal strain was significantly lower in the cancer patients. Strain rate analysis of LA phasic function showed that LA function during systole and early diastole was reduced in the cancer group, while it was increased during late diastole. These findings indicated that LA reservoir and conduit functions, assessed with LA volumetric and strain analysis, were deteriorated in the cancer group. On the other hand, LA booster pump function was elevated in the cancer group in comparison with the controls. In the whole population, cancer was associated with reduced LA total longitudinal strain independently of age, gender, BMI, LV hypertrophy, E/e' ratio, diabetes, and hypertension. LA phasic function was impaired in the chemo- and radiotherapy-naive cancer patients in comparison with the control group. Cancer, LV hypertrophy, and hypertension were associated with reduced LA longitudinal strain independently of other important clinical parameters.

Diastolic stress test echocardiography in patients with suspected heart failure with preserved ejection fraction: a pilot study.

AIMS: The purpose of this pilot study was to assess the potential usefulness of diastolic stress test (DST) echocardiography in patients with suspected heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Patients with suspected HFpEF (left ventricular ejection fraction ≥ 50%, exertional dyspnoea, septal E/e' at rest 9-14, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at rest < 220 pg/mL; n = 13) and a control group constituted from asymptomatic patients with arterial hypertension (n = 19) and healthy subjects (n = 18) were included. All patients were analysed by two-dimensional and Doppler echocardiography at rest and during exercise (DST) and underwent cardiopulmonary exercise testing and NT-proBNP analysis during exercise. HFpEF during exercise was defined as exertional dyspnoea and peak VO2  ≤ 20.0 mL/min/kg. In patients with suspected HFpEF at rest, 84.6% of these patients developed HFpEF during exercise, whereas in the group of asymptomatic patients with hypertension and healthy subjects, the rate of developed HFpEF during exercise was 0%. Regarding the diagnostic performance of DST to detect HFpEF during exercise, an E/e' ratio >15 during exercise was the most accurate parameter to detect HFpEF (accuracy 86%), albeit a low sensitivity (45.5%). Nonetheless, combining E/e' with tricuspid regurgitation (TR) velocity > 2.8 m/s during exercise provided a significant increase in the sensitivity to detect patients with HFpEF during exercise (sensitivity 72.7%, specificity 79.5%, and accuracy 78%). Consistent with these findings, an increase of E/e' was significantly linked to worse peak VO2 , and the combination of an increase of both E/e' and TR velocity was associated with elevated NT-proBNP values during exercise. CONCLUSIONS: The findings of this pilot study suggest that DST using E/e' ratio and TR velocity could be of potential usefulness to diagnose HFpEF during exercise in patients with suspected HFpEF at rest.

Early detection of cardiac alterations by left atrial strain in patients with risk for cardiac abnormalities with preserved left ventricular systolic and diastolic function.

This study sought to examine whether early cardiac alterations could be detected by left atrial (LA) strain in patients with risk for cardiac abnormalities. In this cross-sectional and retrospective study, we included patients with (n = 234) and without (n = 48) risk for cardiac abnormalities (i.e. those with arterial hypertension, diabetes mellitus and/or a history of coronary artery disease) of similar age and with preserved left ventricular (LV) systolic and diastolic function according to standard criteria. LA strain was significantly altered in patients with risk for cardiac abnormalities in comparison to those without risk (29.2 ± 8.6 vs. 38.5 ± 12.6%; rate of impaired LA strain: 18.8% vs. 0%; all p < 0.01) and was the most sensitive parameter to detect early LA alterations in comparison with other LA functional parameters (rate of impaired LA strain rate, LA total emptying fraction, and LA expansion index 3.8%, 7.3%, and 3.8%, respectively). Moreover, in patients with risk for cardiac abnormalities LA strain was altered even in the absence of subtle LV systolic and diastolic alterations (rates 13.9% and 6.8%), albeit to a lesser extent than in patients with an abnormal LV longitudinal systolic strain or abnormal mitral annular e' velocities (rates 48.5% and 24.4%). Regarding the clinical relevance of these findings, an impaired LA strain (i.e. < 23%) was significantly linked to exertional dyspnea (OR 3.5 [1.7-7.0]) even adjusting the analyses by age, gender and subtle LV abnormalities. In conclusion, the findings from this study suggest that LA strain measurements could be useful to detect early cardiac alterations in patients with risk for cardiac abnormalities with preserved LV systolic and diastolic function and that these early LA strain alterations could be linked to exertional dyspnea.

Lower limit of normality and clinical relevance of left ventricular early diastolic strain rate for the detection of left ventricular diastolic dysfunction.

Aims: The aim of the present study was to determine the lower limit of normality and the clinical relevance of left ventricular (LV) early diastolic strain rate (LVSRe) for the detection of LV diastolic dysfunction (LVDD). Methods and results: Using 2D speckle-tracking echocardiography, we analysed 377 healthy subjects and 475 patients with risk for LVDD with preserved LV ejection fraction (LVEF). The normal range of LVSRe analysing the healthy subjects was 1.56 ± 0.28 s-1, with a lower limit of normality at 1.00 s-1. Using this cut-off, LVSRe was able to detect high rates of LV diastolic alterations (rate 71.1%), which was significantly better than using indirect diastolic parameters such as left atrial volume index (LAVI) and tricuspid regurgitation velocity (TR) (rates 22.9% and 9.1%) and similar to annular mitral parameters such as lateral and septal e' velocity (rates 70.9% and 72.4%). In line, adding LVSRe to the current evaluation of LVDD increased significantly the rate of detection of LVDD (absolute rate of increase 18.9%; rate of detection of LVDD: from 14.3% to 33.2%, P < 0.01). Regarding the clinical relevance of LVSRe, patients with abnormal LVSRe (i.e. <1.00 s-1) had significantly worse New York Heart Association functional class and symptomatic status than those with normal LVSRe. In addition, in a retrospective post hoc analysis, we found that an abnormal LVSRe had a significant association with the risk of heart failure hospitalization at 2 years (odds ratio 5.0, 95% confidence interval 1.3-18.4), which was better than using conventional diastolic parameters such as septal and lateral e' velocity, LAVI and TR velocity. Conclusion: The findings from this multicentre study provide important data regarding the normal range of LVSRe and highlight the potential clinical relevance of using this new diastolic parameter in the detection of LVDD in patients with preserved LVEF.