N-terminal pro-B-type natriuretic peptide levels vary by ethnicity and are associated with insulin sensitivity after gestational diabetes mellitus.

BACKGROUND: Individuals of South Asian origin have a greater risk of cardiovascular disease after gestational diabetes mellitus (GDM) than European individuals. B-type natriuretic peptide (BNP) and the amino-terminal fragment of its prohormone (NT-proBNP) are commonly used for heart failure screening and diagnosis, but biologically BNP exerts several beneficial cardiovascular effects primarily by counteracting the renin-angiotensin-aldosterone-system. We asked whether ethnic differences in circulating NT-proBNP levels could be explained by the differences in cardiometabolic and inflammatory risk markers? METHODS: We examined 162 South Asian and 107 Nordic women in Norway 1-3 years after GDM with a clinical examination, fasting blood samples and an oral glucose tolerance test. We measured the levels of NT-proBNP, high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), leptin, adiponectin and markers of insulin sensitivity, such as the Matsuda insulin sensitivity index (ISI). Finally, we tried to identify which independent covariate best mediated the ethnic differences in NT-proBNP. RESULTS: The mean (SD) age was 35.3 (4.5) years, BMI 29.1 (6.0) kg/m2, waist-height ratio 0.60 (0.08) and 164 women (61%) had prediabetes/diabetes. Notably, South Asian women had lower levels of NT-proBNP than Nordic women in both the normoglycemic and prediabetes/diabetes groups (median (IQR) 26  (15-38)  vs. 42 (22-66) ng/L, p < 0.001). Higher NT-proBNP levels were associated with greater insulin sensitivity in both South Asian and Nordic women (p = 0.005 and p < 0.001). South Asian women had higher levels of hsCRP (median (IQR) 2.2 (1.1-4.4) vs. 1.2 (0.3-4.2) mg/L), IL-6 (2.3 (1.5-3.2) vs. 1.5 (1.5-2.5) pg/mL), leptin (1647 (1176-2480) vs. 1223 (876-2313) pmol/L), and lower adiponectin levels (7.2 (5.3-9.3) vs. 10.0 (7.2-13.5) mg/L) and Matsuda ISI (2.4 (1.7-3.7) vs. 4.2 (2.9-6.1), pall<0.01) than Nordic women. Even after adjusting for these differences, higher NT-proBNP levels remained associated with insulin sensitivity (22% higher NT-proBNP per SD Matsuda ISI, p = 0.015). Insulin sensitivity and adiponectin mediated 53% and 41% of the ethnic difference in NT-proBNP. CONCLUSIONS: NT-proBNP levels are lower in South Asian than in Nordic women after GDM. Lower NT-proBNP levels correlate with impaired insulin sensitivity. Lower NT-proBNP levels in South Asian women could, therefore, be attributed to impaired insulin sensitivity rather than total body fat.

Digital tools in heart failure: addressing unmet needs.

This Series paper provides an overview of digital tools in heart failure care, encompassing screening, early diagnosis, treatment initiation and optimisation, and monitoring, and the implications these tools could have for research. The current medical environment favours the implementation of digital tools in heart failure due to rapid advancements in technology and computing power, unprecedented global connectivity, and the paradigm shift towards digitisation. Despite available effective therapies for heart failure, substantial inadequacies in managing the condition have hindered improvements in patient outcomes, particularly in low-income and middle-income countries. As digital health tools continue to evolve and exert a growing influence on both clinical care and research, establishing clinical frameworks and supportive ecosystems that enable their effective use on a global scale is crucial.

Changes in 6-min walk test is an independent predictor of death in chronic heart failure with reduced ejection fraction.

AIMS: Functional capacity provides important clinical information in patients with heart failure (HF) and reduced ejection fraction (HFrEF). The 6-min walk test (6MWT) is a simple and inexpensive tool for assessing functional capacity and risk. Although change in 6MWT is frequently used as a surrogate outcome in HF trials, the association with mortality is unclear. We aimed to assess the prognostic importance of changes in 6MWT. METHODS AND RESULTS: Patients with chronic HFrEF referred to HF outpatient clinics in Norway completed a 6MWT at the first visit (baseline) and at a stable follow-up visit after treatment optimization (follow-up). Absolute and relative changes in 6MWT were analysed in association with mortality risk using Cox regression models and flexible cubic splines. The study included 3636 HFrEF patients aged 67.3 ± 11.6 years, 23% women, with left ventricular ejection fraction 30 ± 7%. At baseline, mean 6MWT was 438 ± 125 m, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1574 (732-3093) ng/L, and 27% had New York Heart Association (NYHA) class III/IV. After optimization of guideline-directed medical therapy (median 147 [86-240] days), 6MWT increased by mean 40 ± 74 m, NT-proBNP decreased by median 425 (14-1322) ng/L, and NYHA class improved in 38% of patients. Patients with greater improvements in 6MWT were younger, with greater improvements in NYHA class (r = 0.27, p < 0.001) and larger reductions in NT-proBNP concentrations (r = 0.19, p < 0.001). After mean 845 ± 595 days, 419 (11.5%) patients were dead. Both absolute and relative changes in 6MWT were non-linearly associated with survival, attenuating as 6MWT increased. A 50 m increase in 6MWT was associated with a 17% lower mortality risk (hazard ratio 0.84, 95% confidence interval 0.77-0.90, p < 0.001) in the fully adjusted model, including changes in NYHA class, NT-proBNP concentrations, and other established risk factors. The associations were more pronounced in patients with lower baseline 6MWT and higher age. CONCLUSION: Improvement in 6MWT in patients with HFrEF is associated with increased survival, independent of changes in NT-proBNP and NYHA class. These findings support 6MWT change as a surrogate outcome in HF trials.

Concordance of left ventricular volumes and function measurements between two human readers, a fully automated AI algorithm, and the 3D heart model.

Background: Echocardiography is essential in cardiovascular medicine for screening, diagnosis, and monitoring. Artificial intelligence (AI) has the potential to improve echocardiography by reducing variability and analysis time. While 3D echocardiography is becoming more accurate, 2D imaging still dominates clinical care. We aimed to evaluate agreement in measures of left ventricular (LV) volumes and function between human readers, a fully automated AI 2D algorithm, and the 3D Heart Model. Methods: A retrospective analysis was conducted on 109 patients who underwent 2D and 3D transthoracic echocardiography. LV end-diastolic and end-systolic volumes (LVEDV, LVESV) and ejection fraction (LVEF) were measured by two operators, a commercially available AI algorithm (US2ai), and the 3D Heart Model. Global longitudinal strain (GLS) was measured by the integrated semi-automated software and the AI algorithm. Outcomes included measures of agreement [bias, limit of agreement and Pearson's correlation (R)]. Results: For LV volume measurements, the AI algorithm was strongly correlated with the average of the human operators (r = 0.89 for LVEDV and r = 0.92 for LVESV), which was higher than between the operators (r = 0.74 and r = 0.84, respectively, p < 0.01). The same trend was seen for measures of reliability with respect to LVEDV, but not LVESV. AI demonstrated comparable performance to human operators in measuring LVEF, while the 3D Heart Model had a weaker correlation and reliability compared with human operators and AI measurements. The correlation between human operators and AI for GLS was only moderate. Conclusion: This study demonstrates AI-based echocardiography as a promising tool for accurately assessing LV volumes and LVEF in clinical practice. AI-based measures demonstrated a significantly lower inter-operator variability, thereby improving the consistency and reliability of these assessments. Moreover, AI may prove particularly effective for conducting retrospective bulk analyses, offering a valuable tool for comprehensive evaluations of past data.

Associations Between Biomarkers of Myocardial Injury and Systemic Inflammation and Risk of Incident Ventricular Arrhythmia.

BACKGROUND: Cardiac troponins (cTns) and biomarkers of inflammation are elevated in heart failure (HF) and predict cardiovascular risk. Whether these biomarkers associate with risk of ventricular arrhythmias (VAs) is unclear. OBJECTIVES: This study sought to assess whether cTnT, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations are associated with incident VA. METHODS: In a prospective, observational study of patients treated with implantable cardioverter-defibrillator, cTnT, GDF-15, IL-6, and CRP were measured at baseline and after 1.4 ± 0.5 years and were associated with implantable cardioverter-defibrillator-detected incident VA, HF hospitalizations, and mortality. RESULTS: This study included 489 patients aged 66 ± 12 years and 83% were men. Median concentrations of cTnT were 15 (Q1-Q3: 9-25) ng/L at inclusion, and higher concentrations were associated with higher age, male sex, diabetes mellitus, coronary artery disease, and HF. During 3.1 ± 0.7 years of follow-up, 137 patients (28%) had ≥1 VA. cTnT concentrations were associated with an increased VA risk (per log-unit, HR: 1.63; 95% CI: 1.31-2.01; P < 0.001), also after adjustment for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction (P < 0.001). GDF-15, IL-6, and CRP concentrations were not associated with incident VA, but all (including cTnT) were associated with HF hospitalization and mortality. Changes in cTnT, GDF-15, IL-6, and CRP from baseline to 1.4 years were not associated with subsequent VA. CONCLUSIONS: Higher concentrations of cTnT, GDF-15, IL-6, and CRP associate with HF hospitalization and death, but only cTnT predict incident VA. These findings suggest that myocardial injury rather than inflammation may play a pathophysiological role in VA and sudden cardiac death.

Trajectory of cardiac troponin T following moderate-to-severe COVID-19 and the association with cardiac abnormalities.

BACKGROUND: COVID-19 has been associated with cardiac troponin T (cTnT) elevations and changes in cardiac structure and function, but the link between cardiac dysfunction and high-sensitive cardiac troponin T (hs-cTnT) in the acute and convalescent phase is unclear. OBJECTIVE: To assess whether hs-cTnT concentrations are associated with cardiac dysfunction and structural abnormalities after hospitalization for COVID-19, and to evaluate the performance of hs-cTnT to rule out cardiac pathology. METHODS: Patients hospitalized with COVID-19 had hs-cTnT measured during the index hospitalization and after 3-and 12 months, when they also underwent an echocardiographic study. A subset also underwent cardiovascular magnetic resonance imaging (CMR) after 6 months. Cardiac abnormalities were defined as left ventricular hypertrophy or dysfunction, right ventricular dysfunction, or CMR late gadolinium. RESULTS: We included 189 patients with hs-cTnT concentrations measured during hospitalization for COVID-19, and after 3-and 12 months: Geometric mean (95%CI) 13 (11-15) ng/L, 7 (6-8) ng/L and 7 (6-8) ng/L, respectively. Cardiac abnormalities after 3 months were present in 45 (30%) and 3 (8%) of patients with hs-cTnT ≥ and < 5 ng/L at 3 months, respectively (negative predictive value 92.3% [95%CI 88.5-96.1%]). The performance was similar in patients with and without dyspnea. Hs-cTnT decreased from hospitalization to 3 months (more pronounced in intensive care unit-treated patients) and remained unchanged from 3 to 12 months, regardless of the presence of cardiac abnormalities. CONCLUSION: Higher hs-cTnT concentrations in the convalescent phase of COVID-19 are associated with the presence of cardiac pathology and low concentrations (< 5 ng/L) may support in ruling out cardiac pathology following the infection.

Trans-Cardiac Gradient of Secretoneurin in Patients with Takotsubo Syndrome.

INTRODUCTION: Secretoneurin (SN) is a novel biomarker that provides prognostic information in patients with cardiovascular disease. In experimental models, SN production is increased in the failing myocardium. Currently, no information is available on SN production in human myocardium. Accordingly, we wanted to determine the trans-cardiac gradient of SN in patients with Takotsubo syndrome (TTS), and to correlate circulating SN concentrations with indices of cardiac structure and function. METHODS: We included 15 women diagnosed with TTS according to established criteria. Plasma SN concentrations were measured in blood samples obtained simultaneously from the aortic root and the coronary sinus. Coronary physiology was assessed by invasive measurements, and we used cardiac magnetic resonance imaging to determine left ventricular ejection fraction (LVEF) and cardiac mass. RESULTS: Median age was 65 years and median LVEF was 45%. Median SN concentration was 39 (25th-75th percentile 31-44) pmol/L in the coronary sinus and 37 (30-41) pmol/L in the aortic root (p = 0.02 for difference). SN concentrations in the aortic root showed the highest correlations with N-terminal B-type natriuretic peptide (rho = 0.47) and estimated glomerular filtration rate (rho = -0.41). In contrast, we found weak correlations between SN concentrations and index of myocardial resistance (rho = 0.12), LVEF (rho = 0.08), and cardiac mass (rho = -0.09). CONCLUSION: We demonstrate a positive trans-cardiac gradient of SN in patients with TTS, which supports the hypothesis that SN is produced and released in the human myocardium in situations of myocardial dysfunction and stress.

External validation of a deep learning algorithm for automated echocardiographic strain measurements.

Aims: Echocardiographic strain imaging reflects myocardial deformation and is a sensitive measure of cardiac function and wall-motion abnormalities. Deep learning (DL) algorithms could automate the interpretation of echocardiographic strain imaging. Methods and results: We developed and trained an automated DL-based algorithm for left ventricular (LV) strain measurements in an internal dataset. Global longitudinal strain (GLS) was validated externally in (i) a real-world Taiwanese cohort of participants with and without heart failure (HF), (ii) a core-lab measured dataset from the multinational prevalence of microvascular dysfunction-HF and preserved ejection fraction (PROMIS-HFpEF) study, and regional strain in (iii) the HMC-QU-MI study of patients with suspected myocardial infarction. Outcomes included measures of agreement [bias, mean absolute difference (MAD), root-mean-squared-error (RMSE), and Pearson's correlation (R)] and area under the curve (AUC) to identify HF and regional wall-motion abnormalities. The DL workflow successfully analysed 3741 (89%) studies in the Taiwanese cohort, 176 (96%) in PROMIS-HFpEF, and 158 (98%) in HMC-QU-MI. Automated GLS showed good agreement with manual measurements (mean ± SD): -18.9 ± 4.5% vs. -18.2 ± 4.4%, respectively, bias 0.68 ± 2.52%, MAD 2.0 ± 1.67, RMSE = 2.61, R = 0.84 in the Taiwanese cohort; and -15.4 ± 4.1% vs. -15.9 ± 3.6%, respectively, bias -0.65 ± 2.71%, MAD 2.19 ± 1.71, RMSE = 2.78, R = 0.76 in PROMIS-HFpEF. In the Taiwanese cohort, automated GLS accurately identified patients with HF (AUC = 0.89 for total HF and AUC = 0.98 for HF with reduced ejection fraction). In HMC-QU-MI, automated regional strain identified regional wall-motion abnormalities with an average AUC = 0.80. Conclusion: DL algorithms can interpret echocardiographic strain images with similar accuracy as conventional measurements. These results highlight the potential of DL algorithms to democratize the use of cardiac strain measurements and reduce time-spent and costs for echo labs globally.

Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development.

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk factors, or left ventricular size and function, including matricellular (e.g. SPON1, MFAP4), senescence-associated (FSTL3, IGFBP7), and inflammatory (SVEP1, CCL15, ITIH3) proteins. Protein co-regulation network analyses identified 5 modules associated with HF risk, two of which were influenced by genetic variants that implicated trans hotspots within the VTN and CFH genes.

Early versus delayed coronary angiography in patients with out-of-hospital cardiac arrest and no ST-segment elevation: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Recent randomized controlled trials did not show benefit of early/immediate coronary angiography (CAG) over a delayed/selective strategy in patients with out-of-hospital cardiac arrest (OHCA) and no ST-segment elevation. However, whether selected subgroups, specifically those with a high pretest probability of coronary artery disease may benefit from early CAG remains unclear. METHODS: We included all randomized controlled trials that compared a strategy of early/immediate versus delayed/selective CAG in OHCA patients and no ST elevation and had a follow-up of at least 30 days. The primary outcome of interest was all-cause death. Odds ratios (OR) were calculated and pooled across trials. Interaction testing was used to assess for heterogeneity of treatment effects. RESULTS: In total, 1512 patients (67 years, 26% female, 23% prior myocardial infarction) were included from 5 randomized controlled trials. Early/immediate versus delayed/selective CAG was not associated with a statistically significant difference in odds of death (OR 1.12, 95%-CI 0.91-1.38), with similar findings for the composite outcome of all-cause death or neurological deficit (OR 1.10, 95%-CI 0.89-1.36). There was no effect modification for death by age, presence of a shockable initial cardiac rhythm, history of coronary artery disease, presence of an ischemic event as the presumed cause of arrest, or time to return of spontaneous circulation (all P-interaction > 0.10). However, early/immediate CAG tended to be associated with higher odds of death in women (OR 1.52, 95%-CI 1.00-2.31, P = 0.050) than in men (OR 1.04, 95%-CI 0.82-1.33, P = 0.74; P-interaction 0.097). CONCLUSION: In OHCA patients without ST-segment elevation, a strategy of early/immediate versus delayed/selective CAG did not reduce all-cause mortality across major subgroups. However, women tended to have higher odds of death with early CAG.

Soluble ST2 in Heart Failure: A Clinical Role beyond B-Type Natriuretic Peptide.

Soluble (s)ST2 has been proposed as a useful biomarker for heart failure (HF) patient management. Myocardial damage or mechanical stress stimulate sST2 release. ST2 competes with a membrane bound receptor (ST2 ligand, or ST2L) for interleukin-33 (IL-33) binding, inhibiting the effects induced by the ST2L/IL-33 interaction so that excessive sST2 may contribute to myocardial fibrosis and ventricular remodeling. Compared to natriuretic peptides (NPs), sST2 concentration is not substantially affected by age, sex, body mass index, kidney function, atrial fibrillation, anemia, or HF etiology, and has low intra-individual variation. Its prognostic role as an independent marker is well reported in the literature. However, there is a gap on its use in combination with NPs, currently the only biomarkers recommended by European and American guidelines for HF management. Reflecting the activation of two distinct biological systems, a benefit from the use of sST2 and NP in combination is advocated. The aim of this review is to report the current scientific knowledge on sST2 in the acute and chronic HF settings with a particular attention to its additive role to natriuretic peptides (NPs).

Recent successes in heart failure treatment.

Remarkable recent advances have revolutionized the field of heart failure. Survival has improved among individuals with heart failure and a reduced ejection fraction and for the first time, new therapies have been shown to improve outcomes across the entire ejection fraction spectrum of heart failure. Great strides have been taken in the treatment of specific cardiomyopathies such as cardiac amyloidosis and hypertrophic cardiomyopathy, whereby conditions once considered incurable can now be effectively managed with novel genetic and molecular approaches. Yet there remain substantial residual unmet needs in heart failure. The translation of successful clinical trials to improved patient outcomes is limited by large gaps in implementation of care, widespread lack of disease awareness and poor understanding of the socioeconomic determinants of outcomes and how to address disparities. Ongoing clinical trials, advances in phenotype segmentation for precision medicine and the rise in technology solutions all offer hope for the future.

Changes in mid-regional pro-adrenomedullin during treatment with sacubitril/valsartan.

AIMS: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment. METHODS AND RESULTS: Mid-regional pro-adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nmol/L in HFrEF and 0.88 (0.68-1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status. CONCLUSIONS: MR-proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure. CLINICAL TRIAL REGISTRATION: PROVE-HF ClinicalTrials.gov Identifier: NCT02887183, PARAMOUNT ClinicalTrials.gov Identifier: NCT00887588.