The Association between Placenta Accreta Spectrum Severity and Incidence of Small for Gestational Age Neonates.

OBJECTIVE: The aim of the study is to evaluate whether pathologic severity of placenta accreta spectrum (PAS) is correlated with the incidence of small for gestational age (SGA) and neonatal birthweight. STUDY DESIGN: This was a multicenter cohort study of viable, non-anomalous, singleton gestations delivered with histology-proven PAS. Data including maternal history, neonatal birthweight, and placental pathology were collected and deidentified. Pathology was defined as accreta, increta, or percreta. The primary outcome was rate of SGA defined by birth weight less than the 10th percentile. The secondary outcomes included incidence of large for gestational age (LGA) babies as defined by birth weight greater than the 90th percentile as well as incidence of SGA and LGA in preterm and term gestations. Statistical analysis was performed using Chi-square, Kruskal-Wallis, and log-binomial regression. Increta and percreta patients were each compared with accreta patients. RESULTS: Among the cohort of 1,008 women from seven United States centers, 865 subjects were included in the analysis. The relative risk (RR) of SGA for increta and percreta did not differ from accreta after adjusting for confounders (adjusted RR = 0.63, 95% confidence interval [CI]: 0.36-1.10 for increta and aRR = 0.72, 95% CI: 0.45-1.16 for percreta). The results were stratified by placenta previa status, which did not affect results. There was no difference in incidence of LGA (p = 1.0) by PAS pathologic severity. The incidence of SGA for all PAS patients was 9.2% for those delivered preterm and 18.7% for those delivered at term (p = 0.004). The incidence of LGA for all PAS patients was 12.6% for those delivered preterm and 13.2% for those delivered at term (p = 0.8203). CONCLUSION: There was no difference in incidence of SGA or LGA when comparing accreta to increta or percreta patients regardless of previa status. Although we cannot suggest causation, our results suggest that PAS, regardless of pathologic severity, is not associated with pathologic fetal growth in the preterm period. KEY POINTS: · PAS severity is not associated with SGA in the preterm period.. · PAS severity is not associated with LGA.. · Placenta previa does not affect the incidence of SGA in women with PAS..

Using an Environmentally Friendly Disposal Bag to Discard Leftover Opioids After Gynecologic Surgery.

OBJECTIVE: To evaluate the effects of an environmentally friendly drug deactivation bag on opioid disposal among patients undergoing gynecologic surgery. METHODS: This prospective cohort study included patients undergoing gynecologic procedures requiring an opioid prescription from March 2020 to December 2020. Patients were managed on a restrictive opioid prescribing algorithm and given an opioid disposal bag. The carbon drug deactivation bag neutralizes the opioid medication and can be discarded safely in the trash. Patients were educated about pain management goals and the disposal bag. Patients were surveyed at their postoperative visit to evaluate satisfaction, number of leftover pills, and disposal methods. Statistical analysis was performed using SPSS Statistics 26. RESULTS: Two hundred patients were asked to complete the survey, with a response rate of 78%. The most common procedures were exploratory laparotomy (50%) and minimally invasive hysterectomy (41%). Most patients (91%, 95% CI 91-97) filled their opioid prescription and 64 (41%, 95% CI 34-48) had leftover opioid pills. Most patients with leftover opioid pills (73%, 95% CI 67-79) discarded them; 78%, 95% CI 69-80 used the disposal bag. Patients undergoing an exploratory laparotomy most commonly used the disposal bag. All patients who used the disposal bag stated they would use it again. CONCLUSION: Despite a restrictive opioid prescribing algorithm, 41% of gynecologic surgical patients had leftover opioid pills. This study demonstrated that leftover opioid pills were safely discarded 73% of the time when patients were provided an opioid disposal bag and preoperative education.

Impact of time to surgery from injury on postoperative infection and deep vein thrombosis in periprosthetic knee fractures.

PURPOSE: Periprosthetic fracture (PPF) is a serious complication that occurs in 0.3%-2.5% of all total knee arthroplasties used to treat end-stage arthritis. To our knowledge, there are no studies in the literature that evaluate the association between time to surgery after PPF and early postoperative infections or deep vein thrombosis (DVT). This study tests our hypothesis that delayed time to surgery increases rates of postoperative infection and DVT after PPF surgery. METHODS: Our study cohort included patients undergoing PPF surgery in the American College of Surgeons National Surgical Quality Improvement Program database (2006-2015). The patients were dichotomized based on time to surgery: group 1 with time ≤2 days and group 2 with time >2 days. A 2-by-2 contingency table and Fisher's exact test were used to evaluate the association between complications and time to surgery groups, and multivariate logistic regression was used to adjust for demographics and known risk factors. RESULTS: A total of 263 patients (80% females) with a mean age of 73.9 ± 12.0 years were identified receiving PPF surgery, among which 216 patients were in group 1 and 47 patients in group 2. Complications in group 1 included 3 (1.4%) superficial infections (SI), 1 (0.5%) organ space infection (OSI), 1 (0.5%) wound dehiscence (WD), and 4 (1.9%) deep vein thrombosis (DVT); while complications in group 2 included 1 (2.1%) SI, 1 (2.1%) OSI, 1 (2.1%) DVT, and no WD. No significant difference was detected in postoperative complications between the two groups. However, patients in group 2 were more likely (p = 0.0013) to receive blood transfusions (57.5%) than those in group 1 (32.4%). CONCLUSION: Our study indicates patients with delayed time to surgery have higher chance to receive blood transfusions, but no significant difference in postoperative complications (SI, OSI, WD, or DVT) between the two groups.

Reverse Remodeling and Prognosis Following Kidney Transplantation in Contemporary Patients With Cardiac Dysfunction.

BACKGROUND: Cardiac dysfunction influences candidate selection for kidney transplantation. There is a paucity of data regarding predictors of myocardial recovery following kidney transplantation and long-term outcomes. OBJECTIVES: The purpose of this study was to identify the extent of reverse remodeling in our kidney transplant population and the predictors of such changes, and to assess outcomes in these patients. METHODS: We reviewed 232 patients who underwent kidney transplantation at the Cleveland Clinic from 2003 to 2013 and who had baseline and post-transplant echocardiograms; patients with simultaneous heart transplantation were excluded. RESULTS: Post-transplantation mean left ventricular ejection fraction (LVEF) improved in those with LV dysfunction (increased from 41% to 50%; p < 0.0001; n = 66). There was significant improvement in other parameters, including diastolic function, LV end-diastolic dimension, LV mass, and right ventricular systolic pressure. After adjusting for multiple clinical variables, increased hemoglobin following transplantation was associated with an improved LVEF (odds ratio: 1.50; 95% confidence interval [CI]: 1.07 to 2.14; p = 0.016) and reduced mortality (hazard ratio [HR]: 0.65; 95% CI: 0.49 to 0.87; p = 0.004). An improved LVEF ≥10% predicted survival independently of a pre-transplantation LVEF (HR: 0.46; 95% CI: 0.21 to 0.93; p = 0.031). CONCLUSIONS: Kidney transplantation is associated with improved cardiac structure and function. A rise in post-transplantation hemoglobin was a significant factor associated with such changes, in addition to conferring a survival advantage.

Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure.

BACKGROUND: Plasma levels of cardiotonic steroids are elevated in volume-expanded states, such as chronic kidney disease, but the role of these natriuretic hormones in subjects with heart failure (HF) is unclear. We sought to determine the prognostic role of the cardiotonic steroids marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes. METHODS AND RESULTS: We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 patients with HF. All-cause mortality, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort, median (interquartile range) MBG was 583 (383-812) pM. Higher MBG was associated with higher myeloperoxidase (r=0.42, P<0.0001), B-type natriuretic peptide (r=0.25, P=0.001), and asymmetrical dimethylarginine (r=0.32, P<0.001). Elevated levels of MBG were associated with measures of worse right ventricular function (RV s', r=-0.39, P<0.0001) and predicted increased risk of adverse clinical outcomes (MBG≥574 pmol/L: hazard ratio 1.58 [1.10-2.31], P=0.014) even after adjustment for age, sex, diabetes mellitus, and ischemic pathogenesis. In mice, a left anterior descending coronary artery ligation model of HF lead to increases in MBG, whereas infusion of MBG into mice for 4 weeks lead to significant increases in myeloperoxidase, asymmetrical dimethylarginine, and cardiac fibrosis. CONCLUSIONS: In the setting of HF, elevated plasma levels of MBG are associated with right ventricular dysfunction and predict worse long-term clinical outcomes in multivariable models adjusting for established clinical and biochemical risk factors. Infusion of MBG seems to directly contribute to increased nitrative stress and cardiac fibrosis.

Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure.

BACKGROUND: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). METHODS AND RESULTS: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) µmol/L, 10.9 (8.4-14.0) µmol/L, and 43.8 (37.1-53.0) µmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] µmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] µmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). CONCLUSION: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.

Prognostic significance of left atrial appendage "sludge" in patients with atrial fibrillation: a new transesophageal echocardiographic thromboembolic risk factor.

BACKGROUND: When stratifying thromboembolic risk to patients with atrial fibrillation (AF), left atrial appendage (LAA) thrombus is currently the only echocardiographic index that absolutely contraindicates cardioversion. The aim of this study was to identify the predictors of LAA "sludge" and its impact on subsequent thromboembolism and survival in patients with AF. METHODS: A total of 340 patients (mean age, 66 ± 12 years; 75% men) who underwent transesophageal echocardiography to exclude LAA thrombus before electrical cardioversion or radiofrequency pulmonary vein isolation) for AF were retrospectively studied. LAA sludge was defined as a dynamic, viscid, layered echodensity without a discrete mass, visualized throughout the cardiac cycle. Follow-up was obtained after a mean of 6.7 ± 3.7 years, and patients were analyzed according to LAA thrombus (n = 62 [18%]), sludge (n = 47 [14%]), or spontaneous echocardiographic contrast (n = 84 [25%]). Patients without these transesophageal echocardiographic characteristics served as controls (n = 147 [43%]). RESULTS: LAA sludge was independently predicted by enlarged left atrial area (odds ratio, 4.54; 95% confidence interval [CI], 2.38-8.67; P < .001), reduced LAA emptying velocity (odds ratio, 12.7; 95% CI, 6.11-26.44; P < .001), and reduced left ventricular ejection fraction (odds ratio, 2.11; 95% CI, 1.03-4.32; P < .001). Thromboembolic event and all-cause mortality rates in patients with sludge were 23% and 57%, respectively. Multiple logistic regression analyses identified the presence of LAA sludge to be independently associated with thromboembolic complications (adjusted hazard ratio, 3.43; 95% CI, 1.42-8.28; P = .006) and all-cause mortality (adjusted hazard ratio, 2.02; 95% CI, 1.22-3.36; P = .007). CONCLUSION: Sludge within the LAA is independently associated with subsequent thromboembolic events and all-cause mortality in patients with AF.

Usefulness of elevated urine neopterin levels in assessing cardiac dysfunction and exercise ventilation inefficiency in patients with chronic systolic heart failure.

Neopterin is synthesized by macrophages upon stimulation with gamma-interferon, and high neopterin production is associated with cellular immune activation and increased production of reactive oxygen species (oxidant stress), but the clinical utility of urine neopterin levels in patients with heart failure (HF) has not been explored. Fifty-three ambulatory patients with chronic systolic HF (left ventricular [LV] ejection fraction ≤40%) underwent comprehensive echocardiographic evaluation and cardiopulmonary exercise testing. Urine neopterin levels were quantified by liquid chromatography with tandem mass spectrometric analyses and corrected to urine creatinine (Cr) levels. In our study cohort, median urine neopterin level was 60 µmol/mol Cr (interquartile range 40 to 86). There were modest correlations between urine neopterin levels and abnormalities in cardiac structure and function by echocardiography: LV ejection fraction (r = -0.33, p = 0.017), indexed LV end-diastolic volume (r = 0.31, p = 0.029), indexed LV end-systolic volume (r = 0.32, p = 0.024), and E/septal Ea (r = 0.28, p = 0.041). Although there was no significant correlation between urine neopterin and maximal oxygen uptake (peak VO2: r = -0.25, p = 0.07), there was a modest correlation between urine neopterin and maximal ventilation/carbon dioxide production ratio (VE/VCO2 max: r = 0.38, p = 0.005). In conclusion, increase in urine neopterin levels tracks with disease severity in patients with chronic systolic HF.

Insufficient natriuretic response to continuous intravenous furosemide is associated with poor long-term outcomes in acute decompensated heart failure.

BACKGROUND: Treatment of acute decompensated heart failure (ADHF) with loop diuretics, such as furosemide, is frequently complicated by insufficient urine sodium excretion. We hypothesize that insufficient natriuretic response to diuretic therapy, characterized by lower urine sodium (UNa) and urine furosemide, is associated with subsequent inadequate decongestion, worsening renal function, and adverse long term events. METHODS AND RESULTS: We enrolled 52 consecutive patients with ADHF and measured serum and urine sodium (UNa), urine creatinine (UCr), and urine furosemide (UFurosemide) levels on a spot sample taken after treatment with continuous intravenous furosemide, and followed clinical and renal variables as well as adverse long-term clinical outcomes (death, rehospitalizations, and cardiac transplantation). We observed similar correlations between UNa:UFurosemide ratio and UNa and fractional excretion of sodium (FENa) with 24-hour net urine output (r = 0.52-0.64, all P < .01) and 24-hour weight loss (r = 0.44-0.56; all P < .01). Interestingly, FENa (but not UNa or UNa:UFurosemide) were influenced by estimated glomerular filtration rate (eGFR). We observed an association between lower UNa:UFurosemide with greater likelihood of worsening renal function (hazard ratio [HR] 3.01; P = .02) and poorer adverse clinical outcomes (HR 1.63, P = .008) after adjusting for age and eGFR. Meanwhile, both diminished weight loss and net fluid output over 24 hours of continuous intravenous furosemide were observed when UNa:UFurosemide ratios were <2 mmol/mg or when UNa <50 mmol. CONCLUSION: In patients with ADHF receiving continuous furosemide infusion, impaired natriuretic response to furosemide is associated with greater likelihood of worsening renal function and future adverse long-term outcomes, independently from and incrementally with decreasing intrinsic glomerular filtration.

Right ventricular global longitudinal strain provides prognostic value incremental to left ventricular ejection fraction in patients with heart failure.

BACKGROUND: Right ventricular (RV) global longitudinal strain (RV strain) is a sensitive measure of RV mechanics. Its relationship with standard clinical markers and long-term events in chronic systolic heart failure is not well established. The aim of this study was to examine the ability of RV strain to provide incremental prognostic value to left ventricular (LV) ejection fraction (LVEF) in patients with chronic systolic heart failure. METHODS: In 171 patients with chronic systolic heart failure (LVEF ≤ 35%), a retrospective substudy of RV strain was performed using Velocity Vector Imaging to analyze previously recorded, comprehensive echocardiographic images. Death, cardiac transplantation, and heart failure hospitalization were tracked for 5 years. RESULTS: In this study cohort (mean age, 57 ± 14 years; mean LVEF, 25 ± 6%), mean RV strain was -11.6 ± 5.4%. More impaired RV strain was associated with increasing New York Heart Association class (rank-sums P < .0001) and greater LV volume (LV end-systolic volume index: r = 0.35, P < .0001). Worse RV strain was associated with reduced LVEF (r = -0.45, P < .0001), worse LV diastolic dysfunction (E/e' septal: r = 0.19, P = .017; left atrial volume index: r = 0.18, P = .031), and standard indices of RV systolic and diastolic dysfunction (RV s': r = -0.43, P < .0001; RV e'/a': r = 0.16, P = .0040; right atrial volume index: r = 0.20, P = .015). RV strain predicted long-term adverse events (hazard ratio, 1.30; 95% confidence interval, 1.02-1.70; P = .037). Furthermore, RV strain ≥ -14.8% predicted adverse events after adjustment for age, LVEF, RV s', E/e' septal, and right atrial volume index. CONCLUSION: In patients with chronic systolic heart failure, worse RV strain provides prognostic value incremental to LV function.

Increasing serum soluble angiotensin-converting enzyme 2 activity after intensive medical therapy is associated with better prognosis in acute decompensated heart failure.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system that has been recently identified in circulating form. We aimed to investigate the relationship among changes in soluble ACE2 (sACE2) activity, myocardial performance, and long-term clinical outcomes in patients with acute decompensated heart failure (ADHF). We hypothesized that increasing sACE2 activity levels during intensive medical treatment are associated with improved myocardial performance and long-term clinical outcomes. METHODS AND RESULTS: In 70 patients admitted to the intensive care unit with ADHF, serum sACE2 activity levels, echocardiographic data, and hemodynamic variables were collected within 12 hours of admission (n = 70) and 48-72 hours after intensive medical treatment (n = 57). The median [interquartile range] baseline and 48-72-hour serum sACE2 activity levels were 32 [23-43] ng/mL and 40 [28-60] ng/mL, respectively. Baseline serum sACE2 activity levels correlated with surrogate measures of right ventricular diastolic dysfunction, including right atrial volume index (RAVi; r = 0.31; P = .010), tricuspid E/A ratio (r = 0.39; P = .007), and B-type natriuretic peptide (r = 0.32; P = .008). However, there were no correlations between serum sACE2 and left ventricular systolic or diastolic dysfunction. After intensive medical therapy, a 50% increase in baseline serum sACE2 levels predicted a significant reduction in risk of death, cardiac transplantation, or ADHF rehospitalization, including after adjustment for baseline age, RAVi, and BNP levels (hazard ratio 0.35, 95% confidence interval 0.12-0.84; P = .018). CONCLUSIONS: In patients admitted with ADHF, increasing serum sACE2 activity levels during intensive medical therapy predict improved outcomes independently from underlying cardiac indices.

Novel urinary biomarkers in detecting acute kidney injury, persistent renal impairment, and all-cause mortality following decongestive therapy in acute decompensated heart failure.

BACKGROUND: New urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18), are proposed to allow a more reliable early diagnosis and prognosis of acute kidney injury (AKI) in acute decompensated heart failure (ADHF). Our aim was to compare the predictive value of urinary NGAL, KIM-1, and IL-18 for the occurrence of AKI, persistent renal impairment, and mortality in ADHF. METHODS AND RESULTS: Eighty-three patients admitted for ADHF were analyzed. Urinary creatinine (Cr), NGAL, KIM-1, and IL-18 were measured at baseline. Serum Cr was measured daily during the next 4 days and again at outpatient follow-up after 6 months. Mortality data were prospectively collected. Urinary NGAL, KIM-1, and IL-18 were modestly correlated with each other (Spearman ρ ≤0.61) and poorly correlated with estimated glomerular filtration rate (eGFR; Spearman ρ ≤0.28). None predicted AKI, defined as a 25% decrease in eGFR, during the index hospitalization, but urinary IL-18/Cr was the strongest predictor of persistently elevated serum Cr ≥0.3 mg/dL after 6 months compared with baseline (area under the receiver operating characteristic curve 0.674; P = .013). Urinary IL-18 was also significantly associated with all-cause mortality (hazard ratio 1.48, 95% confidence interval 1.16-1.87; P = .001). CONCLUSIONS: Like urinary NGAL, urinary KIM-1 and IL-18 are relatively modest predictors of AKI in ADHF. Among these novel renal biomarkers examined, further investigations regarding the prognostic value of urinary IL-18 are warranted.

Efficacy of the CHADS2 scoring system to assess left atrial thrombogenic milieu risk before cardioversion of non-valvular atrial fibrillation.

The CHADS2 scoring system was found to be a good predictor for risk stratification of stroke in patients with atrial fibrillation. The effectiveness of this scoring system in assessing thrombogenic milieu before direct-current cardioversion has not yet fully been established on a large scale. In this study, data from 2,369 consecutive patients in whom transesophageal echocardiography was performed for screening before direct-current cardioversion from 1999 to 2008 were analyzed. Left atrial (LA) or LA appendage (LAA) thrombogenic milieu (spontaneous echo contrast, sludge, and thrombus) was investigated. The results were correlated with CHADS2 score findings. The mean age was 66 ± 13 years, and the ratio of men to women was 2.2:1. CHADS2 scores of 0, 1, 2, 3, 4, 5 and 6 were present in 11%, 25%, 30%, 22%, 8%, 3%, and 1% of the studies, respectively. The prevalence of LA or LAA sludge or thrombus increased with increasing CHADS2 scores (2.3%, 7%, 8.5%, 9.9%, 12.3%, and 14.1% for scores of 0, 1, 2, 3, 4, and 5 or 6, respectively, p = 0.01). In a multivariate model, an ejection fraction ≤20% was the best predictor of LA or LAA sludge or thrombus (odds ratio 2.99, p <0.001). In conclusion, transesophageal echocardiographic markers of thrombogenic milieu were highly correlated with increasing CHADS2 scores in patients who underwent transesophageal echocardiography-guided cardioversion. Giving more value to echocardiographic findings, such as the left ventricular ejection fraction, and its different levels (especially an ejection fraction ≤20%) might improve the precision of the CHADS2 scoring scheme to predict thrombogenic milieu in the left atrium or LAA as a surrogate to cardioembolic risk in patients with atrial fibrillation.

Impact of left ventricular diastolic function on left atrial mechanics in systolic heart failure.

The relation between left atrial (LA) mechanics and left ventricular (LV) diastolic function and adverse cardiovascular events are not well established in chronic systolic heart failure (HF). In 108 patients, we performed comprehensive echocardiography with an assessment of LA global longitudinal strain (LAε) by Velocity Vector Imaging. We also performed complete diastolic examinations including mitral inflow, pulmonary vein flow, and tissue Doppler. Death, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort (age 57 ± 15 years, LV ejection fraction 25 ± 6%), mean global LA negative (εnegative), positive (εpositive), and total ε (εtotal) were -6.8 ± 4.4%, 7.7 ± 5.7%, and 14.5 ± 8.2%, respectively. All LAε indexes correlated with individual indexes of LV diastolic dysfunction, including mitral flow early (E) to late diastolic velocity ratio (p <0.05 for all), mitral deceleration time (p <0.01 for all), E to early diastolic velocity of the septal mitral annulus (e') ratio (p <0.05 for all), pulmonary vein flow systolic to diastolic velocity ratio (p <0.001 for all), and maximal LA volume index (p <0.01 for all). All LAε indexes increased across diastolic stage (p <0.001 for all). In multivariate logistic regression analysis, LAεnegative and LAεtotal were associated with the presence of LV diastolic dysfunction grade III even after adjustment for E/e' septal and LA volume index. In Cox proportional hazards analysis, lower magnitude LAεnegative predicted long-term adverse clinical events. In conclusion, more impaired LA mechanics are associated with more severe diastolic dysfunction and predict long-term adverse events in patients with chronic systolic HF.

Protein carbamylation in chronic systolic heart failure: relationship with renal impairment and adverse long-term outcomes.

BACKGROUND: Protein carbamylation, a posttranslational modification promoted during uremia and catalyzed by myeloperoxidase (MPO) at sites of inflammation, is linked to altered protein structure, vascular dysfunction, and poor prognosis. We examine the relationship between plasma protein-bound homocitrulline (PBHCit) levels, a marker of protein lysine residue carbamylation, with cardiorenal function and long-term outcomes in chronic systolic heart failure (HF). METHODS AND RESULTS: In 115 patients with chronic systolic HF (left ventricular ejection fraction ≤35%), we measured plasma PBHCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. In our study cohort, the median PBHCit level was 87 (interquartile range 59-128) µmol/mol lysine. Higher plasma PBHcit levels were associated with poorer renal function (estimated glomerular filtration rate [eGFR]: Spearman r = -0.37; P < .001), cystatin C (r = 0.31; P = .001), and elevated plasma amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (r = 0.26; P = .006), but not with markers of systemic inflammation or oxidant stress (high-sensitivity C-reactive protein and myeloperoxidase [MPO]: P > .10 for each). Furthermore, elevated plasma PBHCit levels were not related to indices of cardiac structure or function (P > .10 for all examined) except modestly with increased right atrial volume index (r = 0.31; P = .002). PBHCit levels predicted adverse long-term events (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.3-2.6; P < .001), including after adjustment for age, eGFR, MPO, and NT-proBNP (HR 1.9, 95% CI 1.2-3.1; P = .006). CONCLUSIONS: In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardiorenal indices of adverse prognosis.

Nitric oxide bioavailability and adiponectin production in chronic systolic heart failure: relation to severity of cardiac dysfunction.

Adiponectin is an anti-inflammatory, antiatherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailability. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA), and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman's r = 0.41, P < 0.001) and aminoterminal pro-B-type natriuretic peptide (NT-proBNP) levels (r = 0.55, P < 0.001), inversely correlated with GABR (r = -0.39, P < 0.001), and were not associated with high-sensitivity C-reactive protein (P = 0.81) or myeloperoxidase (P = 0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r = 0.33, P = 0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sums P = 0.002), right ventricular (RV) systolic dysfunction (rank sums P = 0.002), and RV diastolic dysfunction (rank sums P = 0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (hazard ratio, 95% confidence interval 1.45 [1.02-2.07], P = 0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust in the setting of cardiac dysfunction or elevated natriuretic peptide levels.

Diminished global arginine bioavailability as a metabolic defect in chronic systolic heart failure.

BACKGROUND: Systemic alterations in arginine bioavailability occur in heart failure (HF) patients with more advanced myocardial dysfunction and poorer clinical outcomes, and they improve with beta-blocker therapy. METHODS AND RESULTS: We measured fasting plasma levels of L-arginine and related biogenic amine metabolites in 138 stable symptomatic HF patients with left ventricular ejection fraction ≤35% and comprehensive echocardiographic evaluation. Long-term adverse clinical outcomes (death and cardiac transplantation) were followed for 5 years. Lower global arginine bioavailability ratio (GABR; ratio of L-arginine to L-ornithine + L-citrulline) was associated with higher plasma natriuretic peptide levels, more advanced left ventricular diastolic dysfunction, and more severe right ventricular systolic dysfunction (all P < .001). Patients taking beta-blockers had significantly higher GABR than those not taking beta-blockers (0.86 [interquartile range (IQR) 0.68-1.17] vs 0.61 [0.44-0.89]; P < .001). Subjects with higher GABR experienced fewer long-term adverse clinical events (hazard ratio 0.61 [95% confidence interval 0.43-0.84]; P = .002). In an independent beta-blocker naïve patient cohort, GABR increased following long-term (6 month) beta-blocker therapy (0.89 [IQR 0.52-1.07] to 0.97 [0.81-1.20]; P = .019). CONCLUSIONS: In patients with chronic systolic heart failure, diminished global L-arginine bioavailability is associated with more advanced myocardial dysfunction and poorer long-term adverse clinical outcomes. GABR levels improved with beta-blocker therapy.

Lack of concordance in defining worsening renal function by rise in creatinine vs rise in cystatin C.

Worsening renal function (WRF) during treatment of acute decompensated heart failure (ADHF) is generally associated with adverse outcomes. An increase ≥0.3 mg/dL in creatinine level is widely used as the definition of WRF. The authors sought to determine the level of agreement between WRF based on changes in creatinine and changes in cystatin C (CysC) by analyzing data from 121 ADHF patients with available admission and day 3 creatinine and CysC levels. Admission creatinine and CysC levels were 1.39 (0.98-2.11) mg/dL and 1.95 (1.42-2.69) mg/L, respectively, and correlated well (r=0.81). On average, creatinine (-0.04±0.40 mg/dL) and CysC (0.001±0.34 mg/L) changed minimally from admission to day 3. Although the correlation between both markers on day 3 was still good (r=0.79), the correlation between changes therein was only modest (r=0.43). From the 14 and 15 patients who had WRF based on a ≥0.3 mg/dL increase in creatinine and ≥0.3 mg/L increase in CysC, respectively, only four (about 30%) met both definitions. These observations, together with recent insights in the inconsistencies of creatinine-defined concept of worsening renal function and outcomes, raises the need to research more reliable measures of renal function during treatment of ADHF.

Prognostic implications of relative hypochromia in ambulatory patients with chronic systolic heart failure.

Iron insufficiency has been associated with heart failure, but the impact of a reduction of hemoglobin content in the erythrocytes as estimated by mean corpuscular hemoglobin concentration (MCHC) to myocardial structure, performance, and long-term clinical outcomes has not been well-established. The authors examined hematologic data and long-term outcomes of 197 ambulatory patients with chronic systolic and symptomatic heart failure who underwent comprehensive echocardiographic evaluation. The authors observed that relative hypochromia (defined as low MCHC) was associated with higher natriuretic peptide levels (NT-proBNP, r =-0.40, P<.0001) and lower estimated glomerular filtration rate (eGFR; r = 0.45, P <. 0001) and correlated modestly with indices of left and right ventricular diastolic dysfunction (all P<.05), but were not related to left ventricular ejection fraction (LVEF, r=0.17, P=.079). After 5 years of follow-up, lower MCHC levels were associated with higher risk of death, transplant, or heart failure hospitalization after adjusting for age, LVEF, eGFR, and New York Heart Association class (hazard ratio, 1.34; 95% confidence interval, 1.04-1.72; P=.025), particularly in those with above-median hemoglobin (>13.8 g/dL; hazard ratio, 2.02; 95% confidence interval, 1.44-2.81, P<.0001). Taken together, the observations imply that physicians should take notice of the presence of relative hypochromia particularly in the absence of anemia in the setting of chronic systolic heart failure.

Incremental prognostic value of assessing left ventricular myocardial mechanics in patients with chronic systolic heart failure.

OBJECTIVES: This study sought to examine the ability of left ventricular (LV) global longitudinal strain (GLS) to assess disease severity in patients with chronic systolic heart failure (HF). BACKGROUND: Left ventricular GLS is a sensitive measure of LV mechanics. Its relationship with standard clinical markers and long-term adverse events in chronic systolic HF is not well established. METHODS: In 194 chronic systolic HF patients, we performed comprehensive echocardiography with assessment of GLS by velocity vector imaging averaged from apical 4-chamber and 2-chamber views. Death, cardiac transplantation, and HF hospitalization were tracked for 5 years. RESULTS: In our study cohort (age 57 ± 14 years, left ventricular ejection fraction [LVEF] 26 ± 6%, median N-terminal pro-B-type natriuretic peptide [NT-proBNP] 1,158 pg/ml), the mean GLS was -7.1 ± 3.3%. The GLS worsened with increasing New York Heart Association functional class (rank-sum p < 0.0001) and higher NT-proBNP (r = 0.42, p < 0.0001). The GLS correlated with LV cardiac structure (LV mass index: r = 0.35, p < 0.0001; LV end-diastolic volume index: r = 0.43, p < 0.0001) and LVEF (r = -0.66, p < 0.0001). A lower magnitude of GLS was associated with worsening LV diastolic function (E/e' septal: r = 0.33, p < 0.0001), right ventricular (RV) systolic function (RV s': r = -0.30, p < 0.0001), and RV diastolic function (RV e'/a': r = 0.16, p = 0.033). GLS predicted long-term adverse events (hazard ratio: 1.55, 95% confidence interval: 1.21 to 2.00; p < 0.001). Worsening strain (GLS ≥-6.95%) predicted adverse events after adjustment for age, sex, ischemic etiology, E/e' septal, and NT-proBNP (hazard ratio: 2.04, 95% confidence interval: 1.09 to 3.94; p = 0.025) and age, sex, ischemic etiology, and LVEF (hazard ratio: 2.15, 95% confidence interval: 1.19 to 4.02; p = 0.011). CONCLUSIONS: In chronic systolic HF, worsening LV GLS is associated with more severe LV diastolic dysfunction and RV systolic and diastolic dysfunction, and provides incremental prognostic value to LVEF.