Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely.

Outcome after primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction complicated by cardiogenic shock.

BACKGROUND: Primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS) may reduce the risk of subsequent cardiovascular events but remains challenging. The study aim was to evaluate the clinical characteristics and long-term outcomes of patients undergoing primary PCI for STEMI with CS. METHODS: We conducted an observational cohort study of patients with STEMI who underwent primary PCI between April 2004 and December 2017 at Juntendo University Shizuoka Hospital. The primary outcome was cardiovascular death (CVD) during the median 3-year follow-up. We performed a landmark analysis for the incidence of CVD from 0 day to 1 year and from 1 to 10 years. RESULTS: Among the 1758 STEMI patients in the cohort, 212 (12.1 %) patients with CS showed significantly higher 30-day CVD rate on admission than those without (26.4 % vs 2.9 %). Landmark Kaplan-Meier analysis showed that CVD from day 0 to year 1 was significantly higher in the patients with CS (log-rank p < 0.0001). Multivariate Cox regression analysis showed that CS was significantly associated with higher cardiovascular mortality (adjusted hazard ratio, 11.8; 95%confidence intervals, 7.78-18.1; p < 0.0001), but the mortality rates from 1 to 10 years were comparable (log-rank p = 0.68). CONCLUSION: The cardiovascular 1-year mortality rate for patients with STEMI was higher for those with CS on admission than without, but the mortality rates of >1 year were comparable. Surviving the early phase is essential for patients with STEMI and CS to improve long-term outcomes.

Impact of sleep-disordered breathing on overnight changes in arterial stiffness in patients with acute heart failure.

Overnight increases in arterial stiffness associated with sleep-disordered breathing may adversely affect patients with acute heart failure. Thus, we investigated overnight changes in arterial stiffness and their association with sleep-disordered breathing in patients hospitalized for acute heart failure. Consecutive patients with acute heart failure were enrolled. All participants underwent overnight full polysomnography following the initial improvement of acute signs and symptoms of acute heart failure. The arterial stiffness parameter, cardio-ankle vascular index (CAVI), was assessed before and after polysomnography. Overall, 60 patients (86.7% men) were analyzed. CAVI significantly increased overnight (from 8.4 ± 1.6 at night to 9.1 ± 1.7 in the morning, P < 0.001) in addition to systolic and diastolic blood pressure (from 114.1 mmHg to 121.6 mmHg, P < 0.001; and from 70.1 mmHg to 78.2 mmHg, P < 0.001, respectively). Overnight increase in CAVI (ΔCAVI ≥ 0) was observed in 42 patients (70%). The ΔCAVI ≥ 0 group was likely to have moderate-to-severe sleep-disordered breathing (i.e., apnea-hypopnea index ≥15, 55.6% vs 80.9%, P = 0.047) and greater obstructive respiratory events (29.4% vs 58.5%, P = 0.041). In multivariable analysis, moderate-to-severe sleep-disordered breathing and greater obstructive respiratory events were independently correlated with an overnight increase in CAVI (P = 0.033 and P = 0.042, respectively). In patients hospitalized for acute heart failure, arterial stiffness, as assessed by CAVI, significantly increased overnight. Moderate-to-severe sleep-disordered breathing and obstructive respiratory events may play an important role in the overnight increase in cardio-ankle vascular index.

Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial.

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. FUNDING: Canadian Institutes of Health Research and Philips RS North America.

Diurnal Variations in Serum Uric Acid, Xanthine, and Xanthine Oxidoreductase Activity in Male Patients with Coronary Artery Disease.

Hyperuricemia is influenced by diet and can cause gout. Whether it is a potential risk factor for cardiovascular disease (CVD) remains controversial, and the mechanism is unclear. Similar to CVDs, gout attacks occur more frequently in the morning and at night. A possible reason for this is the diurnal variation in uric acid (UA), However, scientific data regarding this variation in patients with CVD are not available. Thus, we aimed to investigate diurnal variations in serum levels of UA and plasma levels of xanthine, hypoxanthine, and xanthine oxidoreductase (XOR) activity, which were measured at 18:00, 6:00, and 12:00 in male patients with coronary artery disease. Thirty eligible patients participated in the study. UA and xanthine levels significantly increased from 18:00 to 6:00 but significantly decreased from 6:00 to 12:00. By contrast, XOR activity significantly increased both from 18:00 to 6:00 and 6:00 to 12:00. Furthermore, the rates of increase in UA and xanthine levels from night to morning were significantly and positively correlated. In conclusion, UA and xanthine showed similar diurnal variations, whereas XOR activity showed different diurnal variations. The morning UA surge could be due to UA production. The mechanism involved XOR activity, but other factors were also considered.

Prognostic value of estimating appendicular muscle mass in heart failure using creatinine/cystatin C.

BACKGROUND AND AIMS: Heart failure with concomitant sarcopenia has a poor prognosis; therefore, simple methods for evaluating the appendicular skeletal muscle mass index (ASMI) are required. Recently, a model incorporating anthropometric data and the sarcopenia index (i.e., serum creatinine-to-cystatin C ratio [Cre/CysC]), was developed to estimate the ASMI. We hypothesized that this model was superior to the traditional model, which uses only anthropometric data to predict prognosis. This retrospective cohort study compared the prognostic value of low ASMI as defined by the biomarker and anthropometric models in patients with heart failure. METHODS AND RESULTS: Among 847 patients, we estimated ASMI using an anthropometric model (incorporating age, body weight, and height) in 791 patients and a biomarker model (incorporating age, body weight, hemoglobin, and Cre/CysC) in 562 patients. The primary outcome was all-cause mortality. Overall, 53.4% and 39.1% of patients were diagnosed with low ASMI (using the Asian Working Group for Sarcopenia cut-off) by the anthropometric and biomarker models, respectively. The two models showed a poor agreement in the diagnosis of low ASMI (kappa: 0.57, 95% confidence interval: 0.50-0.63). Kaplan-Meier curves showed that a low ASMI was significantly associated with all-cause death in both models. However, this association was retained after adjustment for other covariates in the biomarker model (hazard ratio: 2.32, p = 0.001) but not in the anthropometric model (hazard ratio: 0.79, p = 0.360). CONCLUSION: Among patients hospitalized with heart failure, a low ASMI estimated using the biomarker model, and not the anthropometric model, was significantly associated with all-cause mortality.

Overnight changes in uric acid, xanthine oxidoreductase and oxidative stress levels and their relationships with sleep-disordered breathing in patients with coronary artery disease.

Serum uric acid (UA) level is associated with the high cumulative incidence or prevalence of coronary artery disease (CAD), and hyperuricemia is considered as an independent risk marker for CAD. Sleep-disordered breathing (SDB) is also associated with an increased risk of CAD. Several studies have shown that SDB is associated with hyperuricemia, but the mechanisms are unclear. We measured serum levels of UA and xanthine oxidoreductase (XOR) activity and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), all of which were assessed at 6 p.m. and the following 6 a.m. in males with CAD. In addition, nocturnal pulse oximetry was performed for the night. Overall 32 eligible patients with CAD were enrolled. Serum UA levels significantly increased overnight. (5.32 ± 0.98 mg/dl to 5.46 ± 1.02 mg/dl, p < 0.001) Moreover, XOR activity and urinary 8-OHdG levels significantly increased from 6 p.m. to 6 a.m. Furthermore, 3% Oxygen desaturation index (ODI) was correlated with the overnight changes in XOR activity (r = 0.36, P = 0.047) and urinary 8-OHdG levels (r = 0.41, P = 0.02). In addition, 3%ODI was independently correlated with the changes in XOR activity (correlation coefficient, 0.36; P = 0.047) and 8-OHdG (partial correlation coefficient, 0.63; P = 0.004) in multivariable analyses. SDB severity was associated with the overnight changes in XOR activity and urinary 8-OHdG, suggesting that SDB may be associated with oxidative stress via UA production. This trial is registered at University Hospital Medical Information Network (UMIN), number: UMIN000021624.

Clinical and prognostic implications of hyaluronic acid in hospitalized patients with heart failure.

We investigated the clinical and prognostic implications of hyaluronic acid, a liver fibrosis marker, in patients with heart failure. We measured hyaluronic acid levels on admission in 655 hospitalized patients with heart failure between January 2015 and December 2019. Patients were stratified into three groups according to hyaluronic acid level: low (< 84.3 ng/mL, n = 219), middle (84.3-188.2 ng/mL, n = 218), and high (≥ 188.2 ng/mL, n = 218). The primary endpoint was all-cause death. The high hyaluronic acid group had higher N-terminal pro-brain-type natriuretic peptide levels, larger inferior vena cava, and shorter tricuspid annular plane systolic excursion than the other two groups. During the follow-up period (median 485 days), 132 all-cause deaths were observed: 27 (12.3%) in the low, 37 (17.0%) in the middle, and 68 (31.2%) in the high hyaluronic acid (P < 0.001) groups. Cox proportional hazards analysis revealed that higher log-transformed hyaluronic acid levels were significantly associated with all-cause death (hazard ratio, 1.38; 95% confidence interval, 1.15-1.66; P < 0.001). No significant interaction was observed between hyaluronic acid level and reduced/preserved left ventricular ejection fraction on all-cause death (P = 0.409). Hyaluronic acid provided additional prognostic predictability to pre-existing prognostic factors, including the fibrosis-4 index (continuous net reclassification improvement, 0.232; 95% confidence interval, 0.022-0.441; P = 0.030). In hospitalized patients with heart failure, hyaluronic acid was associated with right ventricular dysfunction and congestion and was independently associated with prognosis regardless of left ventricular ejection fraction.

Prognostic Value of Cheyne-Stokes Respiration and Nutritional Status in Acute Decompensated Heart Failure.

Malnutrition frequently coexists with heart failure (HF), leading to series of negative consequences. Cheyne-Stokes respiration (CSR) is predominantly detected in patients with HF. However, the effect of CSR and malnutrition on the long-term prognosis of patients with acute decompensated HF (ADHF) remains unclear. We enrolled 162 patients with ADHF (median age, 62 years; 78.4% men). The presence of CSR was assessed using polysomnography and the controlling nutritional status score was assessed to evaluate the nutritional status. Patients were divided into four groups based on CSR and malnutrition. The primary outcome was all-cause mortality. In total, 44% of patients had CSR and 67% of patients had malnutrition. The all-cause mortality rate was 26 (16%) during the 35.9 months median follow-up period. CSR with malnutrition was associated with lower survival rates (log-rank p < 0.001). Age, hemoglobin, albumin, lymphocyte count, total cholesterol, triglyceride, low-density lipoprotein cholesterol, creatinine, estimated glomerular filtration rate, B-type natriuretic peptide, administration of loop diuretics, apnea-hypopnea index and central apnea-hypopnea index were significantly different among all groups (p < 0.05). CSR with malnutrition was independently associated with all-cause mortality. In conclusion, CSR with malnutrition is associated with a high risk of all-cause mortality in patients with ADHF.

Multiple Imaging and Surgical Characteristics in Cardiac Metastasis from Undifferentiated Uterine Sarcoma.

Although cardiac metastasis of malignant tumors has often been reported, undifferentiated uterine sarcoma (UUS) is a rare and aggressive uterine tumor. Thus, little is known of the UUS as a primary site of cardiac metastasis. We report a case of a 66-year-old woman, with a history of uterine myoma for 30 years, who was hospitalized with a large uterine tumor and cardiac masses. Although we investigated cardiac masses using imaging modalities, such as ultrasound, cardiac computer tomography, and magnetic resonance imaging, it was challenging to determine the masses as metastasis or thrombi. Cardiac masses were removed by surgery to assess the tissue characteristics and were later identified as tumors due to their appearance. Then, pathological findings revealed that UUS spreads to the right ventricle. We attempted chemotherapy after surgery; however, the disease progressed very quickly and the patient died on the 49th day of admission. In this report, we described the case of a patient with a difficult diagnosis and rapid disease progression of cardiac metastasis from UUS.

Clinical features and predictors of outcome in patients with acute myocardial infarction complicated by out-of-hospital cardiac arrest.

BACKGROUND: Although short-term mortality of acute myocardial infarction (AMI) has decreased dramatically in the past few decades, sudden cardiac arrest remains a serious complication. The aim of the study was to assess the clinical characteristics and predictors of prognosis in AMI patients who experienced out-of-hospital cardiac arrest (OHCA). METHODS: We retrospectively registered consecutive AMI patients who were treated with emergency percutaneous coronary intervention (PCI) between 2004 and 2017. Clinical characteristics and outcomes were compared between patients with OHCA and those without OHCA. RESULTS: Among 2101 AMI patients, 95 (4.7%) presented with OHCA. Younger age (odds ratio [OR]: 0.95; 95% confidence interval [CI]: 0.93-0.97; p < 0.0001), absence of diabetes mellitus (OR, 0.51; 95% CI, 0.30-0.85; p = 0.01) or dyslipidemia (OR, 0.56; 95% CI, 0.36-0.88; p = 0.01), left main trunk (LMT) or left anterior descending artery (LAD) as the culprit lesion (OR, 3.26; 95% CI, 1.99-5.33; p < 0.0001), and renal deficiency (OR, 3.64; 95% CI, 2.27-5.84; p < 0.0001) were significantly associated with incidence of OHCA. Thirty-day mortality was 32.6% in patients with OHCA and 4.5% in those without OHCA. Multivariate logistic analysis revealed LMT or LAD as the culprit lesion (OR, 12.18; 95% CI, 2.27-65.41; p = 0.004), glucose level (OR, 1.01; 95% CI, 1.00-1.01; p = 0.01), and renal deficiency (OR, 3.35; 95% CI, 1.07-10.53; p = 0.04) as independent predictors of 30-day mortality among AMI patients with OHCA. CONCLUSIONS: In patients with AMI who underwent emergency PCI, 30-day mortality was six times greater in those having presented initially with OHCA compared with those without OHCA. Younger age, absence of diabetes mellitus or dyslipidemia, LMT or LAD as the culprit lesion, and renal deficiency were independent predictors of OHCA. OHCA patient with higher blood glucose level on admission, LMT or LAD as the culprit lesion, or renal deficiency showed worse clinical outcomes.

Venous thrombosis via pulmonary arteriovenous malformation causing acute myocardial infarction in a relatively young female patient.

Pulmonary arteriovenous malformation (PAVM) is a probable cause of thromboembolic diseases such as acute myocardial infarction (MI); however, few cases have been reported. A woman in her early 40s developed acute-onset chest pain; an ECG showed ST-elevated MI. Emergency catheter angiography showed that the culprit lesion was a thrombus that was treated successfully with aspiration. She had a history of deep venous thrombosis and CT revealed PAVM. It was likely that the venous thrombus had moved into the coronary artery through the PAVM. Catheter embolisation of the PAVM was performed and she did not experience any other cardiac event until 6 months after embolisation.

Successful Surgical and Endovascular Multidisciplinary Therapy for Mid-aortic Syndrome with Complicated Atherosclerotic Comorbidities in an Older Patient.

Mid-aortic syndrome (MAS) is a rare vascular disorder that causes refractory hypertension. A 76-year-old woman was hospitalized for acute heart failure (HF) with drug-resistant hypertension; other comorbidities included epigastric artery rupture, old myocardial infarction, an intraventricular thrombus, and a cerebral artery aneurysm. Angiography revealed severe narrowing of the descending aorta, which led to the diagnosis of MAS. Although intensive medical treatment improved her HF, optimal blood pressure (BP) could not be achieved. Percutaneous coronary intervention and surgical bypass for diseased aorta was then performed in two stages, resulting in the achievement of optimal BP and alleviation of HF.

Prognostic effect of sleep-disordered breathing on hospitalized patients following acute heart failure.

BACKGROUND: Identifying patients at risk for poor clinical outcomes following acute heart failure (AHF) is essential. However, data regarding the prognostic effect of sleep-disordered breathing (SDB) and treatment with positive airway pressure (PAP) on clinical outcomes of hospitalized patients following AHF is lacking. OBJECTIVES: This study investigated the prognostic effect of SDB, PAP treatment, and compliance with PAP treatment on patient clinical outcomes. Polysomnography was performed in hospitalized patients whose left ventricular ejection fraction was < 50%. Patients were divided into groups based on whether SDB was defined as an apnea-hypopnea index ≥ 15 and if they had received PAP treatment. Furthermore, patients with SDB and PAP were subdivided into more and less compliant groups. We assessed the incidences of deaths and rehospitalizations due to heart failure. RESULTS: Overall, 241 patients were enrolled; 73% had SDB and 29% were initiated on PAP treatment. At a median follow-up of 1.7 years, 74 clinical events (32 deaths, 42 rehospitalizations) occurred. In the multivariable analysis, compared with the non-SDB group, SDB without PAP treatment was associated with an increased risk of clinical outcomes (hazard ratio [HR] 1.79, P = 0.049), whereas SDB with PAP treatment was not (HR 0.78, P = 0.582). Among patients with PAP treatment, a more compliant group was also inversely associated with clinical events (HR 0.11, P = 0.012). CONCLUSIONS: In hospitalized patients with AHF, untreated SDB was associated with worse clinical outcomes that might be reversible by PAP treatment. However, this potential may be suppressed in less compliant patients.

Urinary liver-type fatty acid-binding protein as a prognostic marker in patients with acute heart failure.

AIMS: Urinary liver-type fatty acid-binding protein (L-FABP) is expressed in proximal tubular epithelial cells and excreted into the urine during tubular injury. We hypothesized that high urinary L-FABP is associated with poor prognosis in patients with acute heart failure (AHF). METHODS AND RESULTS: We analysed 623 patients (74 ± 13 years old; 60.0% male patients) with AHF. Urinary L-FABP levels were measured at the time of admission and adjusted for the urinary creatinine concentration. The primary endpoint was all-cause mortality. The median value and interquartile range of urinary L-FABP levels were 6.66 and 3.37-21.1 µg/gCr, respectively. Urinary L-FABP levels were significantly correlated with both beta-2 microglobulin and cystatin C levels; the correlation with the former was higher than that with the latter. During the follow-up of 631 (interquartile range: 387-875) days, 142 deaths occurred. A high tertile of urinary L-FABP level was associated with high mortality; this association was retained after adjusting for other covariates (second tertile hazard ratio 1.40, P = 0.152 vs. first tertile; third tertile hazard ratio 1.94, P = 0.005 vs. first tertile). CONCLUSIONS: Urinary L-FABP is more closely associated with tubular dysfunction than with glomerular dysfunction. Tubular dysfunction, which was evaluated based on urinary L-FABP levels, in patients with AHF is associated with all-cause mortality and is independent of pre-existing risk factors. L-FABP should be considered for use in the prognosis of AHF.

Prevalence and Prognostic Relevance of Isolated Tubular Dysfunction in Patients With Acute Heart Failure.

BACKGROUND: Renal dysfunction includes glomerular dysfunction (GD) and tubular dysfunction (TD); however, there is limited information regarding the prevalence, coexistence, and prognostic relevance of TD and GD among patients with acute heart failure (AHF).Methods and Results:This study reviewed 489 patients with AHF who had undergone testing at the time of their admission to identify GD (estimated glomerular filtration rate <60 mL/min/1.73 m2) and TD (urinary ß-2-microglobulin ≥300 µg/gCr). Patients were grouped according to the presence/absence of GD and TD as having neither condition (n=116), isolated TD (n=101), isolated GD (n=83), or coexisting GD plus TD (n=189). During a median follow up of 466 days (interquartile range: 170-871 days), 107 deaths were observed. Kaplan-Meier curve analysis revealed that, relative to the absence of a GD and TD group, higher mortality rates were observed in the groups with isolated TD, isolated GD, and coexisting GD plus TD (log-rank P<0.001). Similarly, the adjusted Cox regression analyses revealed that significantly higher risks of mortality were associated with isolated TD, isolated GD, and coexisting GD plus TD. Moreover, isolated GD and isolated TD were both independently associated with increased risks of all-cause mortality. CONCLUSIONS: As a significant proportion of patients with AHF had isolated TD and an increased risk of mortality, patients with AHF should be screened for TD even if they do not have GD.

Prognostic effects of arterial carbon dioxide levels in patients hospitalized into the cardiac intensive care unit for acute heart failure.

AIMS: Although both hypercapnia and hypocapnia are common in acute heart failure (AHF) patients, routine assessment of arterial blood gas is not recommended. Additionally, no association between hypercapnia and increased mortality has been found, and the prognostic value of hypocapnia in AHF patients remains to be elucidated. In this observational study, we aimed to investigate the relationship between partial pressure of arterial carbon dioxide (PaCO2), especially low PaCO2, and long-term mortality in AHF patients. METHODS AND RESULTS: Acute heart failure patients hospitalized in the cardiac intensive care unit of our institution between 2007 and 2011 were screened. All eligible patients were divided into two groups based on the inflection point (i.e. 31.0 mmHg) of the 3-knot cubic spline curve of the hazard ratio (HR), with a PaCO2 of 40 mmHg as a reference. The association between PaCO2 levels and all-cause mortality was assessed using Cox proportional hazards regression models. Among 435 patients with a median follow-up of 1.8 years, 115 (26.4%) died. Adjusted analysis with relevant variables as confounders indicated that PaCO2 <31 mmHg was significantly associated with increased all-cause mortality [HR 1.71, 95% confidence interval (CI) 1.05-2.79; P = 0.032]. When PaCO2 was considered as a continuous variable, the lower was the log-transformed PaCO2, the greater was the increased risk of mortality (HR 0.71, 95% CI 0.52-0.96; P = 0.024). CONCLUSIONS: In AHF patients, lower PaCO2 at admission was associated with increased long-term mortality risk.

Temporal changes of cardiac acoustic biomarkers and cardiac function in acute decompensated heart failure.

AIMS: Relationships between cardiac acoustic biomarkers (CABs) measured by acoustic cardiography and clinical outcomes have been reported in heart failure (HF) patients. However, no studies have investigated the temporal change of CABs and the corresponding changes in HF status. The purpose of this study was to assess whether the temporal changes of CABs in patients with acute decompensated heart failure (ADHF) reflect changes in cardiac function and status. METHODS AND RESULTS: Sixty ADHF patients were enrolled prospectively. CABs and echocardiography data were collected at admission, before discharge, and at the first clinic visit. CABs included electromechanical activation time (EMAT); the time interval from Q wave onset on electrocardiography to the first heart sound (S1), QoS2; the time interval from Q wave onset on electrocardiography to the second heart sound (S2); and third heart sound (S3) and fourth heart sound (S4) intensities, defined as the peak-to-peak amplitudes of S3 and S4. EMATc (EMAT/RR) (P = 0.001), S3 intensity (P < 0.001), and S4 intensity (P < 0.001) were significantly decreased, and QoS2 (P = 0.005) was significantly increased from admission to discharge. The change in S3 intensity was significantly correlated with that of E/A (ρ = 0.571, P < 0.001), and the extended QoS2 was also significantly correlated with the increase in the stroke volume index (ρ = 0.383, P = 0.004). CONCLUSIONS: Some CABs in ADHF patients changed significantly in the normal direction throughout the treatment course and could be useful biomarkers in ADHF management.

Successful implantation of a leadless pacemaker in a patient with complete atrioventricular block and congenital absence of superior vena cava: a case report.

BACKGROUND: Congenital absence of superior vena cava (CASVC) is an extremely rare vascular anomaly often associated with conduction disturbances which makes implantation of a pacemaker difficult. We report a case of pacemaker implantation in a patient presenting with complete atrioventricular block (c-AVB) with bilateral absence of the SVC. CASE SUMMARY: A 68-year-old man who had experienced dyspnoea on exertion by c-AVB was admitted to our hospital for treatment and management. Permanent pacemaker insertion was initially planned; however, an endocardial pacemaker lead could not be implanted in the right atrium. Computed tomography scan with contrast revealed that the venous blood from the upper half of the body flowed into the inferior vena cava via the azygos vein. Due to the difficulty of inserting an endocardial lead from the subclavian vein, a leadless pacemaker (LP) was implanted instead via the femoral vein. DISCUSSION: This is the first case of an LP implantation in a patient presenting with c-AVB with CASVC. Confirmation of blood vessel anatomy to rule out CASVC is necessary prior to pacemaker implantation when abnormal venous anatomy is suspected.

Clinical and prognostic values of urinary alpha1-microglobulin as a tubular marker in acute heart failure.

BACKGROUND: Although urinary alpha-1-microglobulin has been used as a marker of tubular dysfunction, its clinical and prognostic values in patients with acute heart failure have not been validated. METHODS: We analyzed 623 patients (74 ± 13 years old, 60.0% male) with acute heart failure in whom urinary alpha-1-microglobulin (A1MG) levels were measured as tubular markers at the time of admission. The primary endpoint was all-cause mortality. RESULTS: The median levels of urinary alpha-1-microglobulin with and without correction for urinary creatinine concentration were 8.80 (interquartile range: 4.20-17.7) mg/dL and 12.9 (5.92-30.7) mg/gCr, respectively. Urinary A1MG levels were significantly correlated with all of beta-2-microglobulin (r = 0.77), N-acetyl-ß-D-glucosaminidase (r = 0.51), and estimated glomerular filtration rate (r = -0.42); however, alpha-1-microglobulin was most often predicted using beta-2-microglobulin or N-acetyl-ß-D-glucosaminidase. During the 488-day (interquartile range: 185-938 days) follow-up, 141 deaths occurred. Higher A1MG levels were associated with higher mortality even after adjustment for other covariates. Only A1MG, but not beta-2-microglobulin or N-acetyl-ß-D-glucosaminidase, yielded incremental prognostic information in addition to the preexisting prognostic factors (net-reclassification improvement: 0.254, P = 0.023; integrated discrimination improvement: 0.015, P = 0.028). CONCLUSIONS: In patients hospitalized due to acute heart failure, urinary alpha-1-microglobulin was a marker of tubular dysfunction. High alpha-1-microglobulin was associated with all-cause mortality independent of glomerular function and was a better predictor of mortality than urinary beta-2-microglobulin.