Elisabeth Pieske-Kraigher

Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study

Aims To determine tolerability and the optimal dose regimen of the soluble guanylate cyclase stimulator vericiguat in patients with chronic heart failure and preserved ejection fraction (HFpEF). Methods and results SOCRATES-PRESERVED was a prospective, randomized, placebo-controlled double-blind, Phase 2b dose-finding study in patients with HFpEF (ejection fraction ≥ 45%). Patients received vericiguat once daily at 1.25 or 2.5 mg fixed doses, or 5 or 10 mg titrated from a 2.5 mg starting dose, or placebo for 12 weeks. The two primary endpoints were change from baseline in log-transformed N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and left atrial volume (LAV) at 12 weeks. Patients (N = 477; 48% women; mean age 73 ± 10 years; baseline atrial fibrillation 40%) were randomized within 4 weeks of HF hospitalization (75%) or outpatient treatment with intravenous diuretics for HF (25%) to vericiguat (n = 384) or placebo (n = 93). In the pooled three highest dose arms change in logNT-proBNP (vericiguat: +0.038 ± 0.782 log(pg/mL), n = 195; placebo: −0.098 ± 0.778 log(pg/mL), n = 73; one-sided P = 0.8991, two-sided P = 0.2017), and change in LAV [vericiguat: −1.7 ± 12.8 mL (n = 194); placebo:  −3.4 ± 12.7 mL (n = 67), one-sided P = 0.8156, two-sided P = 0.3688] were not different from placebo. Vericiguat was well tolerated (adverse events: vericiguat 10 mg arm, 69.8%; placebo, 73.1%), with low discontinuation rates in all groups, and no changes in blood pressure at 10 mg compared with placebo. The pre-specified exploratory endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score improved in the vericiguat 10 mg arm by mean 19.3 ± 16.3 points [median 19.8 (interquartile range 10.4–30.7)] from baseline (mean difference from placebo 9.2 points). Conclusion Vericiguat was well tolerated, did not change NT-proBNP and LAV at 12 weeks compared with placebo but was associated with improvements in quality of life in patients with HFpEF. Given the encouraging results on quality of life, the effects of vericiguat in patients with HFpEF warrant further study, possibly with higher doses, longer follow-up and additional endpoints.

Normal range and usefulness of right ventricular systolic strain to detect subtle right ventricular systolic abnormalities in patients with heart failure: a multicentre study

Aims The aim of the present multicentre study was to analyse a large cohort of healthy subjects and patients with a common condition such as heart failure (HF) with the purpose of determining the normal range and the usefulness of right ventricular (RV) systolic strain to detect subtle RV systolic abnormalities using 2D speckle-tracking echocardiography. Methods and results We analysed 238 healthy subjects and a cohort of 642 patients characterized by asymptomatic patients (n = 216) and patients with HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (n = 218 and n = 208, respectively) prospectively included in 10 centres. The normal range of RV systolic strain analysing the healthy subjects was as follows: RV global strain −24.5 ± 3.8 and RV free wall strain −28.5 ± 4.8 (lowest expected value −17 and −19%, respectively). Concerning the ability of these myocardial parameters to detect subtle RV systolic abnormalities, RV global and free wall systolic strain were able to detect subtle RV longitudinal systolic abnormalities in a significant proportion of patients with HFrEF and to a lesser extent in HFpEF despite preserved tricuspid annular plane systolic excursion, tricuspid lateral annular peak systolic velocity by pulsed tissue Doppler imaging, and RV fractional area change. In addition, RV global and free wall systolic strain were significantly linked to the symptomatic status of the patients. Conclusions The findings from this study provide important data regarding the normal range of RV global and free wall systolic strain and highlight the clinical relevance of these RV myocardial parameters to detect subtle RV systolic abnormalities in patients with HF.

Patient-reported outcomes in the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED ejection fraction (SOCRATES-PRESERVED) study

Exploratory assessment of the potential benefits of the novel soluble guanylate cyclase stimulator vericiguat on health status in patients with heart failure (HF) with preserved ejection fraction.

Left ventricular longitudinal systolic function analysed by 2D speckle-tracking echocardiography in heart failure with preserved ejection fraction: a meta-analysis

Background The purpose of this meta-analysis was to confirm if the global longitudinal systolic function of the left ventricle (LV) is altered in patients with heart failure with preserved ejection fraction (HFpEF). Methods We searched in different databases (Medline, Embase and Cochrane) studies that analysed LV global longitudinal systolic strain (GLS) in patients with HFpEF and in controls (such as healthy subjects or asymptomatic patients with arterial hypertension, diabetes mellitus or coronary artery disease). Results Twenty-two studies (2284 patients with HFpEF and 2302 controls) were included in the final analysis. Patients with HFpEF had significantly lower GLS than healthy subjects (mean −15.7% (range −12% to −18.9%) vs mean −19.9% (range −17.1% to −21.5%), weighted mean difference −4.2% (95% CI −3.3% to −5.0%), p < 0.001, respectively). In addition, patients with HFpEF had also significantly lower GLS than asymptomatic patients (mean −15.5% (range −13.4% to −18.4%) vs mean −18.3% (range −15.1% to −20.4%), weighted mean difference −2.8%(95% CI −1.9% to −3.6%), p < 0.001, respectively). In line, 10 studies showed that the rate of abnormal GLS was significantly higher in patients with HFpEF (mean 65.4% (range 37%–95%)) than in asymptomatic subjects (mean 13% (range 0%–29.6%)). Regarding the prognostic relevance of abnormal GLS in HFpEF, two multicentre studies with large sample size (447 and 348) and high number of events (115 and 177) showed that patients with abnormal GLS had worse cardiovascular (CV) outcomes than those with normal GLS (HR for CV mortality and HF hospitalisation 2.14 (95% CI 1.26 to 3.66) and 1.94 (95% CI 1.22 to 3.07)), even adjusting these analyses for multiples clinical and echocardiographic variables. Conclusion The present meta-analysis analysing 2284 patients with HFpEF and 2302 controls confirms that the longitudinal systolic function of the LV is significantly altered in high proportion of patients with HFpEF. Further large multicentre studies with the aim to confirm the prognostic role of abnormal GLS in HFpEF are warranted.

Relationship between bone turnover and left ventricular function in primary hyperparathyroidism: The EPATH trial

Observational studies suggested a link between bone disease and left ventricular (LV) dysfunction that may be pronounced in hyperparathyroid conditions. We therefore aimed to test the hypothesis that circulating markers of bone turnover correlate with LV function in a cohort of patients with primary hyperparathyroidism (pHPT). Cross-sectional data of 155 subjects with pHPT were analyzed who participated in the “Eplerenone in Primary Hyperparathyroidism” (EPATH) Trial. Multivariate linear regression analyses with LV ejection fraction (LVEF, systolic function) or peak early transmitral filling velocity (e’, diastolic function) as dependent variables and N-terminal propeptide of procollagen type 1 (P1NP), osteocalcin (OC), bone-specific alkaline phosphatase (BALP), or beta-crosslaps (CTX) as the respective independent variable were performed. Analyses were additionally adjusted for plasma parathyroid hormone, plasma calcium, age, sex, HbA1c, body mass index, mean 24-hours systolic blood pressure, smoking status, estimated glomerular filtration rate, antihypertensive treatment, osteoporosis treatment, 25-hydroxy vitamin D and N-terminal pro-brain B-type natriuretic peptide. Independent relationships were observed between P1NP and LVEF (adjusted β-coefficient = 0.201, P = 0.035) and e’ (β = 0.188, P = 0.042), respectively. OC (β = 0.192, P = 0.039) and BALP (β = 0.198, P = 0.030) were each independently related with e’. CTX showed no correlations with LVEF or e’. In conclusion, high bone formation markers were independently and paradoxically related with better LV diastolic and, partly, better systolic function, in the setting of pHPT. Potentially cardio-protective properties of stimulated bone formation in the context of hyperparathyroidism should be explored in future studies.

Left ventricular strain and twisting in heart failure with preserved ejection fraction: an updated review

Despite the high prevalence of the patients with heart failure with preserved ejection fraction (HFpEF), our knowledge about this entity, from diagnostic tools to therapeutic approach, is still not well established. The evaluation of patients with HFpEF is mainly based on echocardiography, as the most widely accepted tool in cardiac imaging. Identification of left ventricular (LV) diastolic dysfunction has long been considered as the only responsible for HFpEF, and its evaluation is still “sine qua non” of HFpEF diagnostics. However, one should be aware of the fact that identifying cardiac dysfunction in HFpEF might be very challenging and often needs more complex evaluation of cardiac structure and function. New echocardiographic modalities such as 2D and 3D speckle tracking imaging could help in the diagnosis of HFpEF and provide further information regarding LV function and mechanics. Early diagnosis, medical management, and adequate monitoring of HFpEF patients are prerequisites of modern medical treatment. New healthcare approaches require individualized patient care, which is why clinicians should have all clinical, laboratory, and diagnostic data before making final decisions about the treatment of any patients. This is particularly important for HFpEF that often remains undiagnosed for quite a long time, which further prolongs the beginning of adequate treatment and brings into question outcome of these patients. The aim of this article is to provide the overview of the main principles of LV mechanics and summarize recent data regarding LV strain in patients with HFpEF.

Exercise training in Diastolic Heart Failure (Ex‐DHF): rationale and design of a multicentre, prospective, randomized, controlled, parallel group trial

Heart failure with preserved ejection fraction (HFpEF) is a common disease with high incidence and increasing prevalence. Patients suffer from functional limitation, poor health‐related quality of life, and reduced prognosis. A pilot study in a smaller group of HFpEF patients showed that structured, supervised exercise training (ET) improves maximal exercise capacity, diastolic function, and physical quality of life. However, the long‐term effects of ET on patient‐related outcomes remain unclear in HFpEF. The primary objective of the Exercise training in Diastolic Heart Failure (Ex‐DHF) trial is to investigate whether a 12 month supervised ET can improve a clinically meaningful composite outcome score in HFpEF patients. Components of the outcome score are all‐cause mortality, hospitalizations, NYHA functional class, global self‐rated health, maximal exercise capacity, and diastolic function. After undergoing baseline assessments to determine whether ET can be performed safely, 320 patients at 11 trial sites with stable HFpEF are randomized 1:1 to supervised ET in addition to usual care or to usual care alone. Patients randomized to ET perform supervised endurance/resistance ET (3 times/week at a certified training centre) for 12 months. At baseline and during follow‐up, anthropometry, echocardiography, cardiopulmonary exercise testing, and health‐related quality of life evaluation are performed. Blood samples are collected to examine various biomarkers. Overall physical activity, training sessions, and adherence are monitored and documented throughout the study using patient diaries, heart rate monitors, and accelerometers. The Ex‐DHF trial is the first multicentre trial to assess the long‐term effects of a supervised ET programme on different outcome measures in patients with HFpEF.

Low-grade inflammation and tryptophan-kynurenine pathway activation are associated with adverse cardiac remodeling in primary hyperparathyroidism: the EPATH trial

Abstract Background: Primary hyperparathyroidism (pHPT) is associated with low-grade inflammation, left ventricular hypertrophy and increased cardiovascular mortality, but the association between inflammatory markers and parameters of adverse cardiac remodeling is unknown. We investigated the relationship between C-reactive protein (CRP), the essential amino acid tryptophan and its pro-inflammatory derivatives kynurenine and quinolinic acid (QUIN) with echocardiographic parameters. Methods: Cross-sectional baseline data from the “Eplerenone in Primary Hyperparathyroidism” trial were analyzed. Patients with any acute illness were excluded. We assessed associations between CRP, serum levels of tryptophan, kynurenine and QUIN and left ventricular mass index (LVMI), left atrial volume index (LAVI) and E/e′. Results: Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%. Multivariate linear regression analyses with LVMI, LAVI and E/e′ as respective dependent variables, and C-reactive protein and tryptophan, kynurenine and QUIN as respective independent variables were performed. Analyses were adjusted for age, sex, blood pressure, parathyroid hormone, calcium and other cardiovascular risk factors. LVMI was independently associated with CRP (adjusted β-coefficient=0.193, p=0.030) and QUIN (β=0.270, p=0.007), but not kynurenine. LAVI was related with CRP (β=0.315, p<0.001), kynurenine (β=0.256, p=0.005) and QUIN (β=0.213, p=0.044). E/e′ was related with kynurenine (β=0.221, p=0.022) and QUIN (β=0.292, p=0.006). Tryptophan was not associated with any of the remodeling parameters. [Correction added after online publication (22 April 2017: The sentence “Among 136 subjects with pHPT (79% females), 100 (73%) had left ventricular hypertrophy.” was corrected to “Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%.”] Conclusions: Cardiac remodeling is common in pHPT and is associated with low-grade inflammation and activation of the tryptophan-kynurenine pathway. The potential role of kynurenine and QUIN as cardiovascular risk factors may be further investigated in future studies.

Prognostic value of non-invasive stress testing for coronary artery disease in obese patients

Detecting coronary artery disease (CAD) in obese patients remains a challenge but can have substantial prognostic implications for this patient group. Until now, sufficient data was not available on which to base the selection of the imaging modality in obese patients. The decision on which imaging modality to use should therefore follow the general guidelines. In this article, the authors discuss the prognostic value of the different non-invasive stress testing methods for CAD in obese patients.

Cardiac anomaly detection based on time and frequency domain features using tree-based classifiers

OBJECTIVE Recent advantages in mHealth-enabled ECG recorders boosted the demand for algorithms, which are able to automatically detect cardiac anomalies with high accuracy. APPROACH We present a combined method of classical signal analysis and machine learning which has been developed during the Computing in Cardiology Challenge (CinC) 2017. Almost 400 hand-crafted features have been developed to reflect the complex physiology of cardiac arrhythmias and their appearance in single-channel ECG recordings. For the scope of this article, we performed several experiments on the publicly available challenge dataset to improve the classification accuracy. We compared the performance of two tree-based algorithms-gradient boosted trees and random forests-using different parameters for learning. We assessed the influence of five different sets of training annotations on the classifiers performance. Further, we present a new web-based ECG viewer to review and correct the training labels of a signal data set. Moreover, we analysed the feature importance and evaluated the model performance when using only a subset of the features. The primary data source used in the analysis was the dataset of the CinC 2017, consisting of 8528 signals from four classes. Our best results were achieved using a gradient boosted tree model which worked significantly better than random forests. MAIN RESULTS Official results of the challenge follow-up phase provided by the Challenge organizers on the full hidden test set are 90.8% (Normal), 84.1% (AF), 74.5% (Other), resulting in a mean F1-score of 83.2%, which was only 1.6% behind the challenge winner and 0.2% ahead of the next-best algorithm. Official results were rounded to two decimal places which lead to the equal-second best F1 F -score of 83% with five others. SIGNIFICANCE The algorithm achieved the second-best score among 80 algorithms of the Challenge follow-up phase equal with five others.