Elevated blood bicarbonate levels and long-term adverse outcomes in patients with chronic heart failure.

AIMS: The bicarbonate (HCO3 -) buffer system is crucial for maintaining acid-base homeostasis and blood pH. Recent studies showed that elevated serum HCO3 - levels serve as an indicator of the beneficial effects of acetazolamide in improving decongestion in acute heart failure. In this study, we sought to clarify the clinical relevance and prognostic impact of HCO3 - in chronic heart failure (CHF). METHODS: This cohort study enrolled 694 hospitalized patients with CHF (mean age 68.6 ± 14.6, 62% male) who underwent arterial blood sampling and exhibited neutral pH ranging from 7.35 to 7.45. We characterized the patients based on HCO3 - levels and followed them to register cardiac events. RESULTS: Among the patients, 17.3% (120 patients) had HCO3 - levels exceeding 26 mmol/L. Patients presenting HCO3 - > 26 mmol/L were more likely to use loop diuretics and had higher serum sodium and lower potassium levels, but left ventricular ejection fraction did not differ compared with those with HCO3 - between 22 and 26 (379 patients) or those with HCO3 - < 22 mmol/L (195 patients). During a median follow-up period of 1950 days, Kaplan-Meier analysis revealed that patients with HCO3 - > 26 mmol/L had the lowest event-free survival rate from either cardiac deaths or heart failure-related rehospitalization (P < 0.01 and 0.03, respectively). In the multivariable Cox model, the presence of HCO3 - > 26 mmol/L independently predicted increased risks of each cardiac event with a hazard ratio of 2.31 and 1.69 (P < 0.01 and 0.02, respectively), while HCO3 - < 22 mmol/L was not associated with these events (hazard ratios, 0.99 and 1.19; P = 0.98 and 0.43, respectively). CONCLUSIONS: Elevated blood HCO3 - levels may signify enhanced proximal nephron activation and loop diuretic resistance, leading to long-term adverse outcomes in patients with CHF, even within a normal pH range.

Neutrophil Extracellular Traps in Myocardial Tissue Drive Cardiac Dysfunction and Adverse Outcomes in Patients With Heart Failure With Dilated Cardiomyopathy.

BACKGROUND: The immune systems and chronic inflammation are implicated in the pathogenesis of dilated cardiomyopathy (DCM) and heart failure. However, the significance of neutrophil extracellular traps (NETs) in heart failure remains to be elucidated. METHODS: We enrolled consecutive 62 patients with heart failure with idiopathic DCM who underwent endomyocardial biopsy. Biopsy specimens were subjected to fluorescent immunostaining to detect NETs, and clinical and outcome data were collected. Ex vivo and in vivo experiments were conducted. RESULTS: The numbers of NETs per myocardial tissue area and the proportion of NETs per neutrophil were significantly higher in patients with DCM compared with non-DCM control subjects without heart failure, and the numbers of NETs were negatively correlated with left ventricular ejection fraction. Patients with DCM with NETs (n=32) showed lower left ventricular ejection fraction and higher BNP (B-type natriuretic peptide) than those without NETs (n=30). In a multivariable Cox proportional hazard model, the presence of NETs was independently associated with an increased risk of adverse cardiac events in patients with DCM. To understand specific underlying mechanisms, extracellular flux analysis in ex vivo revealed that NETs-containing conditioned medium from wild-type neutrophils or purified NET components led to impaired mitochondrial oxygen consumption of cardiomyocytes, while these effects were abolished when PAD4 (peptidyl arginine deiminase 4) in neutrophils was genetically ablated. In a murine model of pressure overload, NETs in myocardial tissue were predominantly detected in the acute phase and persisted throughout the ongoing stress. Four weeks after transverse aortic constriction, left ventricular ejection fraction was reduced in wild-type mice, whereas PAD4-deficient mice displayed preserved left ventricular ejection fraction without inducing NET formation. CONCLUSIONS: NETs in myocardial tissue contribute to cardiac dysfunction and adverse outcomes in patients with heart failure with DCM, potentially through mitochondrial dysfunction of cardiomyocytes.

Collagen Triple Helix Repeat-Containing Protein 1 Is a Novel Biomarker of Right Ventricular Involvement in Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension leads to right ventricular failure, which is a major determinant of prognosis. Circulating biomarkers for right ventricular function are poorly explored in pulmonary hypertension. This study aimed to clarify the significance of collagen triple helix repeat-containing protein 1 (CTHRC1) as a biomarker of right ventricular failure in pulmonary hypertension. METHODS: A monocrotaline-induced pulmonary hypertension rat model was used to evaluate right ventricular CTHRC1 expression and its relationship with fibrosis. Next, human plasma CTHRC1 levels were measured in controls (n = 20), pulmonary arterial hypertension (n = 46), and patients with chronic thromboembolic pulmonary hypertension (CTEPH) (n = 64) before the first and after the final balloon pulmonary angioplasty. RESULTS: CTHRC1 expression was higher in the right ventricles of rats with monocrotaline-induced pulmonary hypertension than in those of controls. CTHRC1 was colocalized with vimentin and associated with fibrosis in the right ventricles. Plasma CTHRC1 levels were higher in human patients with pulmonary arterial hypertension (P = 0.006) and CTEPH (P = 0.011) than in controls. Plasma CTHRC levels were correlated with B-type natriuretic peptide (R = 0.355, P < 0.001), tricuspid lateral annular peak systolic velocity (R = -0.213, P = 0.029), and right ventricular fractional area change (R = -0.225, P = 0.017). Finally, plasma CTHRC1 levels were decreased after the final balloon pulmonary angioplasty (P < 0.001) in CTEPH. CONCLUSIONS: CTHRC1 can be a circulating biomarker associated with right ventricular function and fibrosis in pulmonary hypertension and might reflect the therapeutic efficacy of balloon pulmonary angioplasty in CTEPH.

Chemical shift-encoded MRI with compressed sensing combined with parallel imaging for proton density fat fraction measurement of the lumbar vertebral bone marrow.

We aimed to investigate the accuracy of proton density fat fraction (PDFF) measurement of the lumbar vertebral bone marrow using chemical shift-encoded magnetic resonance imaging (CSE-MRI) with compressed sensing combined with parallel imaging (CSPI). This study recruited a commercially available phantom, and 43 patients. Fully sampled data without CSPI and under-sampled data with CSPI acceleration factors of 2.4, 3.6, and 4.8 were acquired using a 1.5T imaging system. The relationships between PDFF measurements obtained with the no-CSPI acquisition and those obtained with each CSPI acquisition were assessed using Pearson correlation coefficient (r), linear regression analyses, and Bland-Altman analysis. The intra- and inter-observer variabilities of the PDFF measurements were evaluated using the intraclass correlation coefficient. PDFF measurements obtained with all acquisitions showed a significant correlation and strong agreement with the reference PDFF measurement of the phantom. PDFF measurements obtained using CSE-MRI with and without CSPI were positively correlated (all acquisitions: r = 0.99; P < .001). The mean bias was -0.31% to -0.17% with 95% limits of agreement within ±2.02%. The intra- and inter-observer agreements were excellent (intraclass correlation coefficient: 0.988 and 0.981, respectively). A strong agreement and positive correlation were observed between the PDFF measurements obtained using CSE-MRI with and without CSPI. PDFF measurement of the lumbar vertebral bone marrow using CSE-MRI with CSPI can be acquired with a maximum reduction of approximately 75% in the acquisition time compared with a fully sampled acquisition.

Heart Failure Post-Myocardial Infarction Promotes Mammary Tumor Growth Through the NGF-TRKA Pathway.

Background: Epidemiological investigations suggest that patients with heart failure have a higher incidence of cancer; however, the causal role of cardiac disease on cancer progression remains unclear. Objectives: This study aimed to investigate the impact and underlying mechanisms of myocardial infarction (MI)-induced heart failure on tumor cell growth. Methods: We generated a syngeneic mouse model by implanting mammary tumor-derived 4T1 cells into BALB/c mice with MI resulting from ligation of the left anterior descending artery. Results: Mice with MI exhibited increased tumor volume, tumor weight, and Ki67-positive proliferative cells in the tumor tissue compared with the sham-operated mice. Furthermore, RNA sequencing analysis in the tumor tissue revealed significant enrichment of pathways related to tumor progression, particularly the PI3K-AKT pathway in the MI mice. Upregulation of tropomyosin receptor kinase A (TRKA) phosphorylation, an upstream regulator of PI3K-AKT signaling, was observed in the tumor tissue of the MI mice. We also observed elevated levels of circulating nerve growth factor (NGF), a ligand of TRKA, and increased NGF expressions in the myocardium after MI. In in vitro experiments, NGF stimulation led to increased cell proliferation, as well as phosphorylation of TRKA and AKT. Notably, inhibition of TRKA by small interfering RNA or the chemical inhibitor GW441756 effectively blocked these effects. Administration of GW441756 resulted in the suppression of tumor volume and cell proliferation in the MI mice. Conclusions: Our study demonstrates that MI promotes mammary tumor growth through the NGF-TRKA pathway. Consequently, inhibiting TRKA could represent a therapeutic strategy for breast cancer patients concurrently experiencing heart failure after MI.

Predictive Value of Aortic Valve Calcium Volume Measured by Computed Tomography for Paravalvular Leakage After Transcatheter Aortic Valve Implantation.

Paravalvular leakage (PVL) is a complication of transcatheter aortic valve implantation (TAVI) for aortic stenosis, leading to an adverse prognosis. We investigated whether aortic valve calcium volume (Ca-Vol) measured by preoperative cardiac computed tomography had a predictive value for PVL after TAVI using a third-generation self-expandable valve.We retrospectively analyzed 59 consecutive patients who underwent TAVI using a third-generation self-expandable valve. We measured Ca-Vol in the aortic valve and each cusp (non-coronary cusp [NCC], right-coronary cusp [RCC], and left-coronary cusp [LCC]). We divided the patients into 2 groups: a PVL group (32.2%) and a non-PVL group (67.8%). Total Ca-Vol was significantly higher in the PVL group than in the non-PVL group (P < 0.001). Ca-Vol in each cusp was also significantly higher in the PVL group ([NCC] P < 0.001, [RCC] P = 0.001, [LCC] P < 0.001). Univariate logistic regression analysis for PVL indicated that the total and per-cusp Ca-Vols were predictors for PVL (total, odds ratio [OR] 4.0, P < 0.001; NCC, OR 12.5, P = 0.002; RCC, OR 16.0, P = 0.008; LCC, OR 44.5, P < 0.001).Receiver operating characteristic curve analysis of Ca-Vol for predicting PVL revealed the optimal cut-off values of Ca-Vol were 2.4 cm3 for the total, 0.74 cm3 for NCC, 0.73 cm3 for RCC, and 0.56 cm3 for LCC (area under the curve, 0.85, 0.79, 0.76, and 0.83, respectively).Preoperative total, NCC, RCC, and LCC calcium volumes were significant predictors for PVL after TAVI using third-generation self-expandable valves.

Calcium-Phosphorus Product Is Associated with Adverse Prognosis in Hospitalized Patients with Heart Failure and Chronic Kidney Disease.

It has been reported that high levels of calcium-phosphorus (Ca-P) product are an indicator of coronary calcification and mortality risk in patients undergoing chronic hemodialysis. In the present study, we aimed to evaluate the significance of Ca-P product to predict the prognosis of patients with heart failure (HF) and chronic kidney disease (CKD). We conducted a prospective observational study of 793 patients with decompensated HF and CKD, and measured the value of Ca-P product. The cut-off value was obtained from the survival classification and regression tree (CART) analysis to predict post-discharge all-cause mortality and/or worsening HF, and the patients were divided into 2 groups: a high group (Ca-P product > 28, n = 594) and a low group (Ca-P product ≤ 28, n = 199). We compared the patient baseline characteristics and post-discharge prognosis between the 2 groups. The age as well as the prevalence of male sex, ischemic etiology, and anemia were significantly higher in the low group than in the high group. In contrast, there was no difference in echocardiographic parameters between the 2 groups. In the Kaplan-Meier analysis (mean follow-up 1089 days), all-cause mortality and/or worsening HF event rates were higher in the low group than in the high group (log-rank P = 0.001). In the multivariable Cox proportional hazard analysis, lower Ca-P product was found to be an independent predictor of all-cause mortality and/or worsening HF (hazard ratio 0.981, P = 0.031). Lower Ca-P product predicts adverse prognosis in patients with HF and CKD.

Chemical Shift-Encoded MRI of the Lumbar Vertebral Bone Marrow for Detecting Osteoporosis With Low Trabecular Bone Quality in Patients With Breast Cancer Receiving Aromatase Inhibitors.

BACKGROUND: Osteoporosis with low trabecular bone quality (OLB) in patients with breast cancer receiving aromatase inhibitor (AI) therapy is associated with an increased risk of vertebral fractures. The capability of chemical shift-encoded MRI (CSE-MRI) in detecting OLB needs to be investigated. PURPOSE: To assess the diagnostic performance of proton density fat fraction (PDFF) and R2* measurements from CSE-MRI for detecting OLB in postmenopausal women with breast cancer undergoing AI therapy. STUDY TYPE: Prospective. POPULATION: 126 postmenopausal females (mean age: 69.5 ± 8.8 years) receiving AIs (average period: 41.6 ± 26.5 months) after breast cancer surgery. FIELD STRENGTH/SEQUENCE: 1.5-T, three-dimensional CSE-MRI (six echoes), T1-weighted Dixon, short tau inversion recovery, and diffusion-weighted images. ASSESSMENT: Both CSE-MRI and dual-energy x-ray absorptiometry were performed on the same day. Measurements included averaged PDFF, R2*, bone mineral density (BMD), and trabecular bone score (TBS) from L1 to L4 vertebrae. A T-score ≤ -2.5 from BMD measurements indicated osteoporosis, whereas T-scores of ≤ - 2.5 plus TBS ≤-3.7 indicated OLB. The diagnostic performance of PDFF, R2*, and the combination of PDFF and R2* for identifying osteoporosis or OLB was assessed. STATISTICAL TESTS: Student's t-test; Mann-Whitney U test; χ2 or Fisher exact tests; Pearson correlation; multivariate analysis; Receiver operating characteristic (ROC) analysis with the area under the curve (AUC); logistic regression model; intraclass correlation coefficient. A P-value <0.05 was considered statistically significant. RESULTS: For detecting osteoporosis, AUC values were 0.59 (PDFF), 0.66 (R2*), and 0.65 (combined PDFF and R2*). Significant mean differences were noted between patients with and without OLB for PDFF (66.11 ± 5.36 vs. 57.49 ± 6.43) and R2* (46.62 ± 9.24 vs. 63.36 ± 12.44). AUC values for detecting OLB were 0.75 (PDFF), 0.82 (R2*), and 0.84 (combined PDFF and R2*). DATA CONCLUSION: R2* may perform better than PDFF for identifying OLB in patients with breast cancer receiving AIs. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 4.

Geriatric Nutritional Risk Index predicts bleeding event in patients with heart failure.

AIMS: We aimed to elucidate the association between malnutrition and the occurrence of bleeding events in patients with heart failure. METHODS AND RESULTS: We evaluated the nutritional status of patients with heart failure [n = 2044, median (inter-quartile range) age 69.0 (59.0-78.0) years, 1209 (59.1%) males] using the Geriatric Nutritional Risk Index (GNRI). The primary endpoint was a composite of bleeding events such as haemorrhagic stroke or gastrointestinal bleeding. According to the survival classification and regression tree analysis, the accurate cut-off point of GNRI for predicting the primary endpoint was 106.2. We divided the patients into two groups based on GNRI levels: high GNRI group (GNRI ≥ 106.2, n = 606, 29.6%) and low GNRI group (GNRI < 106.2, n = 1438, 70.4%). We compared the patients' characteristics and prognosis between the two groups. The low GNRI group was older [72.0 (63.0-79.0) vs. 63.0 (53.0-73.0) years, P < 0.001] and had a lower prevalence of male sex (56.9% vs. 64.5%, P = 0.001). There were no differences in the use of antiplatelet agents and anticoagulants between the two groups. Levels of B-type natriuretic peptide were higher [321.1 (123.3-667.4) vs. 111.6 (42.6-235.4) pg/mL, P < 0.001] and levels of haemoglobin were lower [12.4 (10.8-13.7) vs. 14.2 (12.9-15.4) g/dL, P < 0.001] in the low GNRI group. The Kaplan-Meier analysis demonstrated that bleeding event rates were higher in the low GNRI group (log-rank P < 0.001). The multivariable Cox proportional hazard analysis revealed that low GNRI (hazard ratio 1.952, 95% confidence interval 1.002-3.805, P = 0.049) was associated with bleeding events. CONCLUSIONS: Heart failure patients with poor nutritional status, determined by GNRI under 106.2, experienced high bleeding event rates. Comprehensive management is required to avoid bleeding event in those populations.