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Abstract Background and Aims Exercise stress echocardiography is recommended as an alternative to invasive testing for diagnosing heart failure with preserved ejection fraction (HFpEF), but an evidence-based operational framework guiding its application is lacking. Methods Patients with chronic unexplained dyspnoea underwent invasive haemodynamic exercise testing with simultaneous echocardiography to test the hypotheses that (i) the current diagnostic algorithms (H2FPEF, HFA-PEFF, and HFpEF-ABA scores) could be enhanced when combined with exercise echocardiography; and (ii) incorporating resting left atrial (LA) compliance (LA reservoir strain divided by E/e′) could further improve diagnostic triage, using separate cut points optimizing sensitivity and specificity. Findings were then validated in an international multicentre cohort. Results Of 482 patients, HFpEF was present in 386 and non-cardiac dyspnoea in 96. Sensitivity to detect HFpEF was only 55%–60% and accuracy 61%–67% using individual diagnostic scores with currently recommended exercise echocardiography. Addition of abnormal resting LA compliance to exercise echocardiography increased sensitivity to 84%–85% but increased the false-positive rate to 31%–43%. Applying separate cut points that optimize specificity and sensitivity (either exercise E/e′ ≥ 13.8 or resting LA compliance ≤1.6% to rule-in HFpEF; both exercise E/e′ < 7.2 and resting LA compliance >4.4% to rule-out HFpEF, remaining patients indeterminate who require invasive testing) improved sensitivity to 95%–99% among definitively classified patients and reduced the number of patients that require invasive exercise testing from ∼60% to ∼30%. Findings were replicated in a multicentre, international validation cohort of patients undergoing rest–exercise echocardiography and invasive exercise testing. Conclusions Currently used non-invasive approaches to HFpEF diagnosis have inadequate sensitivity, indicating that exercise echocardiography cannot supplant invasive testing. Addition of LA strain imaging with optimized rule-in or rule-out values improves diagnostic triage by expanding non-invasive rule-in/rule-out classifications while identifying patients who still require invasive testing in the evaluation of HFpEF.

BACKGROUND: Plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) is commonly used to diagnose heart failure with preserved ejection fraction (HFpEF), but its diagnostic performance in the ambulatory/outpatient setting is unknown because previous studies lacked objective reference standards. METHODS: Among patients with chronic dyspnea, diagnosis of HFpEF or noncardiac dyspnea was determined conclusively by exercise catheterization in a derivation cohort (n=414), multicenter validation cohort 1 (n=560), validation cohort 2 (n=207), and a nonobese Japanese validation cohort 3 (n=77). Optimal NT-proBNP cut points for HFpEF rule out (optimizing sensitivity) and rule in (optimizing specificity) were derived and tested, stratified by obesity and atrial fibrillation. Derived cut points were tested in 3 additional validation cohorts (cohorts 4–6) in whom HFpEF was diagnosed by resting catheterization only (n=260), previous hospitalization for heart failure (n=447), or exercise echocardiography (n=517), respectively. RESULTS: Current recommended rule-out NT-proBNP threshold <125 pg/mL had 82% sensitivity (95% CI, 77%–88%) with a body mass index (BMI) <35 kg/m 2 , decreasing to 67% (95% CI, 58%–77%) with a BMI ≥35 kg/m 2 . A lower rule-out NT-proBNP threshold <50 pg/mL displayed good sensitivity with a BMI <35 kg/m 2 (97% [95% CI, 95%–99%]), with a modest decline in sensitivity with a BMI ≥35 kg/m 2 (86% [95% CI, 79%–93%]); diagnostic thresholds were confirmed in validation cohorts 1 and 2 (91% [95% CI, 88%–95%] and 86% [95% CI, 80%–93%] with a BMI <35 kg/m 2 ; 80% [95% CI, 74%–87%] and 84% [95% CI, 74%–93%] with a BMI ≥35 kg/m 2 ). Current consensus age- and BMI-stratified rule-in thresholds demonstrated only 65% specificity (95% CI, 57%–72%). Rule-in NT-proBNP threshold ≥500 pg/mL had 85% specificity (95% CI, 78%–91%) with a BMI <35 kg/m 2 (87% [95% CI, 80%–94%] and 90% [95% CI, 81%–99%] in validation cohorts), with 100% specificity at a BMI ≥35 kg/m 2 (93% [95% CI, 81%–100%] and 100% in validation cohorts). With a BMI ≥35 kg/m 2 , lower rule-in thresholds (≥220 pg/mL) provided good specificity (88% [95% CI, 73%–100%]; 93% [95% CI, 81%–100%] and 100% in validation cohorts). Findings were consistent in validation cohorts 3 through 6 (sensitivity of <50 pg/mL, 93%–98%; specificity of ≥500 pg/mL, 82%–89%). NT-proBNP provided no incremental discrimination among patients with history of AF; ≥98% of patients with AF and dyspnea were found to have HFpEF in our cohorts. CONCLUSIONS: In patients with chronic unexplained dyspnea, current rule-in and rule-out NT-proBNP diagnostic thresholds lead to unacceptably high error rates, with important interactions by obesity and AF status. In our study, NT-proBNP provided little value in those with AF and dyspnea because the presence of AF is by itself a robust biomarker of HFpEF. Use of separate rule-in and rule-out diagnostic thresholds stratified by BMI reduces miscategorization and can guide more appropriate use of exercise testing for possible HFpEF.

ABSTRACT Aims Elevated left atrial (LA) pressure is a pathophysiologic hallmark of heart failure with preserved ejection fraction (HFpEF). Chronically elevated LA pressure leads to LA enlargement, which may impair LA function and increase pulmonary pressures. We sought to evaluate the relationship between LA volume and pulmonary arterial haemodynamics in patients with HFpEF. Methods and results Data from 85 patients (aged 69 ± 8 years) who underwent exercise right heart catheterization and echocardiography were retrospectively analysed. All had symptoms of heart failure, left ventricular ejection fraction ≥50% and haemodynamic features of HFpEF. Patients were divided into LA volume index-based tertiles (≤34 ml/m2, &gt;34 to ≤45 ml/m2, &gt;45 ml/m2). A subgroup analysis was performed in patients with recorded LA global reservoir strain (n = 60), with reduced strain defined as ≤24%. Age, sex, body surface area and left ventricular ejection fraction were similar between volume groups. LA volume was associated with blunted increases in cardiac output with exercise (padjusted &lt;0.001), higher resting mean pulmonary artery pressure (padjusted = 0.003), with similar wedge pressure (padjusted = 1). Pulmonary vascular resistance (PVR) increased with increasing LA volume (padjusted &lt;0.001). Larger LA volumes featured reduced LA strain (padjusted &lt;0.001), with reduced strain associated with reduced PVR–compliance time (0.34 [0.28–0.40] vs. 0.38 [0.33–0.43], p = 0.03). Conclusion Increasing LA volume may be associated with more advanced pulmonary vascular disease in HFpEF, featuring higher PVR and pulmonary pressures. Reduced LA function, worse at increasing LA volumes, is associated with a disrupted PVR–compliance relationship, further augmenting impaired pulmonary haemodynamics.

Study Design: Retrospective cohort study. Objective: The purposes of this study were to determine the rate of improvement of significant preoperative weakness, identify risk factors for failure to improve, and characterize the motor recovery of individual motor groups. Summary of Background Data: While neck and arm pain reliably improve following anterior cervical discectomy and fusion (ACDF), the frequency and magnitude of motor recovery following ACDF remain unclear. Methods: We performed a retrospective review of patients undergoing 1–4-level ACDF at a single institution between September 2015 and June 2016. Patients were subdivided into 2 groups based upon the presence or absence of significant preoperative weakness, which was defined as a motor grade <4 in any single upper extremity muscle group. Clinical notes were reviewed to determine affected muscle groups, rates of motor recovery, and risk factors for failure to improve. Results: We identified 618 patients for inclusion. Significant preoperative upper extremity weakness was present in 27 patients (4.4%). Postoperatively, 19 of the affected patients (70.3%) experienced complete strength recovery, and 5 patients (18.5%) experienced an improvement in muscle strength to a motor grade ≥4. The rate of motor recovery postoperatively was 85.7% in the triceps, 83.3% in the finger flexors, 83.3% in the hand intrinsics, 50.0% in the biceps, and 25.0% in the deltoids. Risk factors for failure to experience significant motor improvement were the presence of myelomalacia (odds ratio: 28.9, P<0.01) and the performance of >2 levels of ACDF (odds ratio: 10.1, P<0.01). Conclusions: Patients with substantial preoperative upper extremity weakness can expect high rates of motor recovery following ACDF, though patients with deltoid weakness, myelomalacia, and >2 levels of ACDF are less likely to experience significant motor improvement.

Background: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. Methods: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome—a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status—was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. Results: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P =0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P =0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P =0.004). Conclusions: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

Study Design: This was a multicenter retrospective cohort study. Objective: The purpose of this study was to compare the surgical and radiographic outcomes of patients undergoing posterior cervical fusion (PCF) with constructs extending from C2 to T2 to patients with constructs extending from C3 to T1. Summary of Background Data: Limited evidence exists regarding the appropriate level of proximal and distal extension of PCF constructs. Methods: A multicenter retrospective cohort study of patients who underwent PCF between 2012 and 2020 was performed. Surgical and radiographic outcomes were compared between those who had C3–T1 or C2–T2 constructs. Results: A total of 155 patients were included in the study (C2–T2: 106 patients, C3–T1: 49 patients). There were no significant differences in demographics or preoperative symptoms between cohorts. Fusion rates were significantly higher in the C2–T2 (93%) than the C3–T1 (80%, P=0.040) cohort. When comparing the C2–T2 to the C3–T1 cohort, the C3–T1 cohort had a significantly greater rate of proximal junctional failure (2% vs. 10%, P=0.006), distal junctional failure (1% vs. 20%, P<0.001) and distal screw loosening (4% vs. 15%, P=0.02). Although ∆C2–C7 sagittal vertical axis increased significantly in both cohorts (C2–T2: 6.2 mm, P=0.04; C3–T1: 8.4 mm, P<0.001), correction did not significantly differ between groups (P=0.32). The C3–T1 cohort had a significantly greater increase in ∆C2 slope (8.0 vs. 3.1 degrees, P=0.03) and ∆C0–C2 Cobb angle (6.4 vs. 1.2 degrees, P=0.04). Conclusion: In patients undergoing PCF, a C2–T2 construct demonstrated lower rates of pseudarthrosis, distal junctional failure, proximal junctional failure, and compensatory upper cervical hyperextension compared with a C3–T1 construct.

Abstract Aims This study aimed to describe haemodynamic features of patients with advanced heart failure with preserved ejection fraction (HFpEF) as defined by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Methods and results We used pooled data from two dedicated HFpEF studies with invasive exercise haemodynamic protocols, the REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients with Heart Failure) trial and the REDUCE LAP-HF I trial, and categorized patients according to advanced heart failure (AdHF) criteria. The well-characterized HFpEF patients were considered advanced if they had persistent New York Heart Association classification of III–IV and heart failure (HF) hospitalization &lt; 12 months and a 6 min walk test distance &lt; 300 m. Twenty-four (22%) out of 108 patients met the AdHF criteria. On evaluation, clinical characteristics and resting haemodynamics were not different in the two groups. Patients with AdHF had lower work capacity compared with non-advanced patients (35 ± 16 vs. 45 ± 18 W, P = 0.021). Workload-corrected pulmonary capillary wedge pressure normalized to body weight (PCWL) was higher in AdHF patients compared with non-advanced (112 ± 55 vs. 86 ± 49 mmHg/W/kg, P = 0.04). Further, AdHF patients had a smaller increase in cardiac index during exercise (1.1 ± 0.7 vs. 1.6 ± 0.9 L/min/m2, P = 0.028). Conclusions A significantly higher PCWL and lower cardiac index reserve during exercise were observed in AdHF patients compared with non-advanced. These differences were not apparent at rest. Therapies targeting the haemodynamic compromise associated with advanced HFpEF are needed.

Study Design: This was a narrative review. Objective: This review discusses our current knowledge regarding cellular-based allografts while highlighting the key gaps in the literature that must be addressed before their widespread adoption. Summary of Background Data: Iliac crest bone graft is the gold-standard bone graft material but is associated with donor site morbidity. Commonly utilized bone graft extenders such as demineralized bone matrix and bone morphogenetic protein have conflicting data supporting their efficacy and lack the osteogenic potential of new cellular-based allograft options. Methods: An extensive literature review was performed. The literature was then summarized in accordance with the authors’ clinical experience. Results: There is not widespread evidence thus far that the addition of the osteogenic cellular component to allograft enhances spinal fusion, as a recent study by Bhamb and colleagues demonstrated superior bone formation during spine fusion in an aythmic rat model when demineralized bone matrix was used in comparison to Osteocel Plus. Furthermore, the postimplantation cellular viability and osteogenic and osteoinductive capacity of cellular-based allografts need to be definitively established, especially given that a recent study by Lina and colleagues demonstrated a paucity of bone marrow cell survival in an immunocompetent mouse posterolateral spinal fusion model. Conclusions: This data indicates that the substantially increased cost of these cellular allografts may not be justified. Level of Evidence: Level V.