Objectives This study was designed to investigate: 1) relationships between serum ST2 levels and hemodynamic/neurohormonal variables; 2) myocardial ST2 production; and the 3) expression of ST2, ...membrane-anchored ST2L, and its ligand, interleukin (IL)-33, in myocardium, endothelium, and leukocytes from patients with left ventricular (LV) pressure overload and congestive cardiomyopathy. Background Serum levels of ST2 are elevated in heart failure. The relationship of ST2 to hemodynamic variables, source of ST2, and expression of ST2L and IL-33 in the cardiovascular system are unknown. Methods Serum ST2 (pg/ml; median 25th, 75th percentile) was measured in patients with LV hypertrophy (aortic stenosis) (n = 45), congestive cardiomyopathy (n = 53), and controls (n = 23). ST2 was correlated to N-terminal pro-brain natriuretic peptide, C-reactive protein, and hemodynamic variables. Coronary sinus and arterial blood sampling determined myocardial gradient (production) of ST2. The levels of ST2, ST2L, and IL-33 were measured (reverse transcriptase-polymerase chain reaction) in myocardial biopsies and leukocytes. The ST2 protein production was evaluated in human endothelial cells. The IL-33 protein expression was determined (immunohistochemistry) in coronary artery endothelium. Results The ST2 protein was elevated in aortic stenosis (103 65, 165 pg/ml, p < 0.05) and congestive cardiomyopathy (194 69, 551 pg/ml, p < 0.01) versus controls (49 4, 89 pg/ml) and correlated with B-type natriuretic peptide (r = 0.5, p < 0.05), C-reactive protein (r = 0.6, p < 0.01), and LV end-diastolic pressure (r = 0.38, p < 0.03). The LV ST2 messenger ribonucleic acid was similar in aortic stenosis and congestive cardiomyopathy versus control (p = NS). No myocardial ST2 protein gradient was observed. Endothelial cells secreted ST2. The IL-33 protein was expressed in coronary artery endothelium. Leukocyte ST2L and IL-33 levels were highly correlated (r = 0.97, p < 0.001). Conclusions In human hypertrophy and failure, serum ST2 correlates with the diastolic load. Though the heart, endothelium, and leukocytes express components of ST2/ST2L/IL-33 pathway, the source of circulating serum ST2 is extra-myocardial.
This study aimed to examine the relationship between corin expression and circulating brain natriuretic peptide in patients with left ventricular (LV) dysfunction.Circulating levels of B-type ...natriuretic peptide (BNP) can be an indicator of LV dysfunction. The 32-amino-acid BNP is cleaved by corin, a cardiac serine protease, from its108-amino-acid pro-brain natriuretic peptide (proBNP) precursor.This study included 25 patients with idiopathic dilated cardiomyopathy (DCMP) and LV dysfunction and 44 heart transplant recipients with normal LV function who underwent diagnostic left and right heart catheterization. Blood samples were used to determine the ratio of plasma proBNP/BNP levels, and LV endomyocardial biopsies were used to determine the expression of NPPB, which encode BNP and corin, respectively, by quantitative reverse transcription-polymerase chain reaction.Patients with DCMP revealed worse hemodynamic profiles and higher plasma proBNP and BNP levels than those of the transplant recipients. Myocardial NPPB expression was higher and CORIN expression was lower in the DCMP patients than in the transplant recipients. CORIN expression significantly correlated with NPPB expression (r = −0.585; P < 0.001), ejection fraction (EF; r = 0.694; P < 0.01), LV end-diastolic pressure (r = −0.373; P < 0.05), and indexed end-diastolic LV volume (r = −0.452; P < 0.001). In addition, the plasma proBNP/BNP levels inversely correlated with the CORIN expression (r = −0.362; P < 0.005).Decreased myocardial CORIN expression and the corresponding higher levels of circulating unprocessed proBNP in DCMP may partly account for the relative BNP resistance observed in patients with LV dysfunction.
Background The effect of adherence to cardiac rehabilitation (CR) on outcome is not clear. Therefore, we aimed to assess the impact of drop-out for non-medical reasons of CR on event-free survival in ...coronary artery disease (CAD). Methods A total of 876 patients who attended CR after acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) were included. Drop-out was defined as attending ≤50% of the training sessions. A combined endpoint of all-cause mortality and rehospitalization for a cardiovascular event was used to specify event-free survival. Differences in clinical characteristics were assessed and parameters with p < 0.10 were entered in a multiple Cox regression analysis. Results A total of 15% died or had a cardiovascular event during a median follow-up period of 33 months (interquartile range 24, 51). Overall, 17% dropped out before finishing half of the program. Patients who withdrew prematurely had a risk twice as high for a cardiovascular event or death (hazard ratio 1.92, 95% confidence interval 1.28-2.90) than those who attended more than half of the sessions. Both ACS (2.36, 1.47-3.58) and PCI (2.20, 1.22-3.96), as primary indicators for CR, were associated with an adverse outcome and also a prior history of chronic heart failure (CHF) remained negatively associated with event-free survival (3.67, 1.24-10.91). Finally, the presence of hyperlipidemia was independently related to a worse outcome (1.48, 1.02-2.16). Conclusions Drop-out for non-medical reasons was independently associated with a negative outcome in CAD. Therefore, underlying factors for drop-out should gain more attention in future research and should be taken into account when organizing CR.
The additional role of continuous monitoring of filling pressures and impedance in heart failure patients with chronic kidney disease remains undetermined. In this case report, the effects of ...diuretic therapy and renal replacement therapy by hemodialysis upon right ventricular filling pressures and impedance are described in a patient with end-stage heart failure and end-stage chronic kidney disease (grade 5). We demonstrated that unloading of the heart by hemodialysis partly restored the blunted Frank-Starling relationship.
Myocardial Gene Expression in Heart Failure Patients Treated With Cardiac Resynchronization Therapy: Responders Versus Nonresponders Marc Vanderheyden, Wilfried Mullens, Leen Delrue, Marc Goethals, ...Bernard de Bruyne, William Wijns, Peter Geelen, Sofie Verstreken, Francis Wellens, Jozef Bartunek We studied whether functional improvement after cardiac resynchronization therapy (CRT) is associated with reversal of the heart failure gene program. Therefore patients referred for CRT underwent endomyocardial biopsies before CRT and at follow-up for subsequent detection of messenger ribonucleic acid (mRNA) levels of contractile and calcium regulatory genes with quantitative real time polymerase chain reaction. Patients had lower α-myosin heavy chain (MHC), β-MHC, sarcoplasmic reticulum calcium ATPase 2α (SERCA), phospholamban (PLN), and higher brain natriuretic peptide (BNP) gene expression as compared with control subjects. Responders to CRT showed an increase in α-MHC and SERCA, a decrease in BNP mRNA levels, and an increase in the ratio of α-/β-MHC and SERCA/PLN. Functional improvement after CRT is associated with favorable changes in genes regulating contractile function and hypertrophy.
Aims
We investigated the prognostic relevance of serpin peptidase inhibitor, clade A member 3 (SERPINA3) in patients admitted with a de novo or worsened heart failure (HF).
Methods and results
In the ...first stage, 83 HF‐related left ventricular (LV) transcripts were examined in patients with congestive cardiomyopathy (CCMP, n = 44) who died within 5 years and compared with age‐matched and haemodynamically matched CCMP survivors (n = 39) and controls with normal LV function (n = 17). Among 14 differentially expressed transcripts, myocardial gene and circulating SERPINA3 levels were up‐regulated in non‐survivors vs. survivors (2.40 ± 3.66 vs. 0.36 ± 0.22 units, P < 0.01 and 334.7 ± 138.7 vs. 228.2 ± 83.1 μg/mL, P < 0.01, respectively). While no significant transmyocardial gradient was detected, cytokine stimulation of human endothelial cells induced SERPINA3 secretion. In an independent validation cohort with a de novo or worsened HF (n = 387), circulating SERPINA3 levels > 316 μg/mL were associated with increased all‐cause mortality {hazard ratio HR 95% confidence interval (CI): 2.4 1.5–3.9, P = 0.0002} and its composite with unplanned cardiovascular readmission HR (95% CI): 2.0 (1.2–3.3), P = 0.004. Patients with elevated SERPINA3 levels and elevated either N‐terminal pro brain natriuretic peptide or ST2 showed worse freedom from both endpoints. In a multivariate analysis, including established clinical risk factors, SERPINA3 remained independent predictor of all‐cause mortality together with age, gender, ST2, glomerular filtration, and pulmonary capillary wedge pressure.
Conclusion
In patients with a de novo or worsened HF, increased SERPINA3 levels > 316 μg/mL are associated with increased mortality or unplanned cardiac readmission. Elevated SERPINA3 levels on top of established clinical predictors appear to identify a subgroup of HF patients at higher mortality risk. Prospective studies should further validate its value in prognostic stratification of HF.
We postulated that both diastolic and systolic load modulate B-type natriuretic peptide (BNP) production in human pressure overload hypertrophy/failure.
In isolated myocytes, diastolic stretch ...induces BNP messenger ribonucleic acid expression. However, the mechanism of the BNP release in human hypertrophy remains controversial.
In 40 patients with symptomatic aortic stenosis (AS), left ventricular (LV) performance and systolic and diastolic wall stress were calculated from combined invasive and echocardiographic data. Plasma BNP was determined by the rapid point-of-care bedside analyzer (Biosite Triage, Biosite Diagnostics Inc., San Diego, California).
A significant relationship was observed between plasma BNP and pulmonary capillary wedge pressure (p < 0.001), fractional shortening (p = 0.001), and aortic valve area (p = 0.006). Furthermore, a significant correlation was noted between BNP and LV mass index (p = 0.005) as well as between BNP and markers of diastolic load such as LV end-diastolic wall stress (p = 0.011), indexed LV end-diastolic volume (p < 0.001), and isovolumic relaxation time (p = 0.02). Preoperative BNP levels were elevated in patients with AS compared with patients without AS. Plasma BNP was higher in AS patients with impaired versus normal preload reserve (297 ± 56 pg/ml vs. 168 ± 44 pg/ml; p = 0.017) and in AS patients with clinical deterioration after valve replacement compared with those without (399 ± 82 pg/ml vs. 124 ± 41 pg/ml; p = 0.011).
In patients with AS, BNP appears to be regulated not only by systolic but also by diastolic load. This supports the hypothesis that myocardial stretch modulates BNP production in human pressure overload hypertrophy/failure.
Aims
Transthyretin amyloid cardiomyopathy (ATTR‐CM), a progressive and fatal cardiomyopathy, is frequently misdiagnosed or entails diagnostic delays, hindering patients from timely treatment. This ...study aimed to generate a systematic framework based on data from electronic health records (EHRs) to assess patients with ATTR‐CM in a real‐world population of heart failure (HF) patients. Predictive factors or combinations of predictive factors related to ATTR‐CM in a European population were also assessed.
Methods and results
Retrospective unstructured and semi‐structured data from EHRs of patients from OLV Hospital Aalst, Belgium (2012–20), were processed using natural language processing (NLP) to generate an Observational Medical Outcomes Partnership Common Data Model database. NLP model performance was assessed on a random subset of EHRs by comparing algorithm outputs to a physician‐generated standard (using precision, recall, and their harmonic mean, or F1‐score). Of the 3127 HF patients, 103 potentially had ATTR‐CM (age 78 ± 9 years; male 55%; ejection fraction of 48% ± 16). The mean diagnostic delay between HF and ATTR‐CM diagnosis was 1.8 years. Besides HF and cardiomyopathy‐related phenotypes, the strongest cardiac predictor was atrial fibrillation (AF; 72% in ATTR‐CM vs. 60% in non‐ATTR‐CM, P = 0.02), whereas the strongest non‐cardiac predictor was carpal tunnel syndrome (21% in ATTR‐CM vs. 3% in non‐ATTR‐CM, P < 0.001). The strongest combination predictor was AF, joint disorders, and HF with preserved ejection fraction (29% in ATTR‐CM vs. 18% in non‐ATTR‐CM: odds ratio = 2.03, 95% confidence interval = 1.28–3.22).
Conclusions
Not only well‐known variables associated with ATTR‐CM but also unique combinations of cardiac and non‐cardiac phenotypes are able to predict ATTR‐CM in a real‐world HF population, aiding in early identification of ATTR‐CM patients.
Aims
The Cardiovascular Outcomes Retrospective Data analysIS in Heart Failure (CORDIS‐HF) is a single‐centre retrospective study aimed to (i) clinically characterize a real‐world population with ...heart failure (HF) with reduced (HFrEF) and mildly reduced ejection fraction (HFmrEF), (ii) evaluate impact of renal–metabolic comorbidities on all‐cause mortality and HF readmissions, and (iii) determine patients' eligibility for sodium–glucose cotransporter 2 inhibitors (SGLT2is).
Methods and results
Using a natural language processing algorithm, clinical data of patients diagnosed with HFrEF or HFmrEF were retrospectively collected from 2014 to 2018. Mortality and HF readmission events were collected during subsequent 1 and 2 year follow‐up periods. The predictive role of patients' baseline characteristics for outcomes of interest was assessed using univariate and multivariate Cox proportional hazard models. Kaplan–Meier analysis was used to determine if type 2 diabetes (T2D) and chronic kidney disease (CKD) impacted mortality and HF readmission rates. The European SGLT2i label criteria were used to assess patients' eligibility. The CORDIS‐HF included 1333 HF patients with left ventricular ejection fraction (LVEF) < 50% (413 HFmrEF and 920 HFrEF), who were predominantly male (69%) with a mean standard deviation (SD) age of 74.7 (12.3) years. About one‐half (57%) of patients presented CKD and 37% T2D. The use of guideline‐directed medical therapy (GDMT) was high (76–90%). HFrEF patients presented lower age mean (SD): 73.8 (12.4) vs. 76.7 (11.6) years, P < 0.05, higher incidence of coronary artery disease (67% vs. 59%, P < 0.05), lower systolic blood pressure mean (SD): 123 (22.6) vs. 133 (24.0) mmHg, P < 0.05, higher N‐terminal pro‐hormone brain natriuretic peptide (2720 vs. 1920 pg/mL, P < 0.05), and lower estimated glomerular filtration rate mean (SD): 51.4 (23.3) vs. 54.1 (22.3) mL/min/1.73 m2, P < 0.05 than those with HFmrEF. No differences in T2D and CKD were detected. Despite optimal treatment, event rates for the composite endpoint of HF readmission and mortality were 13.7 and 8.4/100 patient years. The presence of T2D and CKD negatively impacted all‐cause mortality T2D: hazard ratio (HR) = 1.49, P < 0.01; CKD: HR = 2.05, P < 0.001 and hospital readmission events in all patients with HF. Eligibility for SGLT2is dapagliflozin and empagliflozin was 86.5% (n = 1153) and 97.9% (n = 1305) of the study population, respectively.
Conclusions
This study identified high residual risk for all‐cause mortality and hospital readmission in real‐world HF patients with LVEF < 50% despite GDMT. T2D and CKD aggravated the risk for these endpoints, indicating the intertwinement of HF with CKD and T2D. SGLT2i treatment that clinically benefits these different disease conditions can be an important driver to lower mortality and hospitalizations in this HF population.
Serial transthoracic echocardiographic (TTE) assessment of LVEF and GLS are the gold standard in screening Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD). Non-invasive left-ventricle (LV) ...pressure-strain loop (PSL) emerged as a novel method to quantify Myocardial Work (MW). This study aims to describe the temporal changes and longitudinal trajectories of MW indices during cardiotoxic treatment. We included 50 breast cancer patients with normal LV function referred for anthracycline therapy w/wo Trastuzumab. Medical therapy, clinical and echocardiographic data were recorded before and 3, 6, and 12 months after initiation of the chemotherapy. MW indices were calculated through PSL analysis. According to ESC guidelines, mild and moderated CTRCD was detected in 10 and 9 patients, respectively (20% CTRCD
, 18% CTRCD
), while 31 patients remained free of CTRCD (62% CTRCD
). Prior to chemotherapy MWI, MWE and CW were significantly lower in CTRCD
than in CTRCD
and CTRCD
. Overt cardiac dysfunction in CTRCD
at 6 months was accompanied by significant worse values in MWI, MWE and WW compared to CTRCD
and CTRCD
. MW features such as low baseline CW, especially when associated with a rise in WW at follow-up, may identify patients at risk for CTRCD. Additional studies are needed to explore the role of MW in CRTCD.
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