Citations

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.

OBJECTIVE Cognard type V dural arteriovenous fistulas (dAVFs), defined by spinal perimedullary venous drainage, represent a rare and aggressive neurovascular pathology. Comprehensive multicenter data remain scarce. The authors present the largest multicenter analysis to date, characterizing presentation, radiology, treatment, complications, and functional outcomes of Cognard type V dAVFs. METHODS The authors retrospectively analyzed patients with angiographically confirmed Cognard type V dAVFs from the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR), spanning 16 academic centers. Patient demographics, imaging features, treatment strategies, procedural complications, and modified Rankin Scale (mRS) scores were recorded. RESULTS Among 1077 patients with dAVFs, 37 (3%) had Cognard type V lesions. The mean patient age was 57 years, and 59.5% of patients were male. Most presented with nonhemorrhagic neurological deficits (68%), while 14% had hemorrhage. The most common location was the foramen magnum (32%). Embolization was the primary treatment in 67% of cases, complete obliteration was achieved in 71% of cases. Upfront microsurgery was performed in 22% of patients (obliteration rate 88%), and radiosurgery in 14% (success rate 40%). Salvage treatment further improved obliteration outcomes. Temporary complications occurred in 8% of patients (3/37): 2 with transient neurological deficits postembolization and 1 with transient hydrocephalus after surgery. Permanent complications were observed in 3% (1/37) due to treatment-related hemorrhage. At the last follow-up (mean 2.4 years), 69% (24/35) of patients maintained or improved to an mRS score ≤ 2. No deaths occurred. Functional improvement was seen in 29% (10/35), while mRS decline was in 40% of patients (14/35), all unrelated to the dAVF itself. CONCLUSIONS Cognard type V dAVFs carry a high risk of neurological morbidity. However, favorable functional outcomes are achievable with timely, multimodal intervention. Complication rates remain low, with most being transient. These data support aggressive but tailored management to prevent permanent disability in this high-risk population.

e15060 Background: In metastatic Breast Cancer (mBC) Circulating Tumor Cells (CTCs) are an established prognostic indicator of patients (pts) with highly aggressive disease, poor clinical outcomes, and poor response rates to therapy. However, CTCs are typically found in < 20% of mBC pts and many pts without CTCs also progress. Cancer associated macrophage-like cells (CAMLs) are inflammatory tumor macrophages also found in blood, in > 90% of mBC, and are indicators of poor clinical outcomes independent of CTCs. We conducted a prospective study to model CTC & CAML subtypes from 212 mBC pt blood samples prior to induction of new systemic therapies to optimize and validate risk models based on 2-year outcomes of Progression-free survival (PFS) & Overall survival (OS). Methods: An observational multi-institutional prospective study was conducted on 212 mBC pts prior to induction of a new line of therapy who were progressing on their current therapy. Anonymized (7.5ml) whole blood samples were taken prior to therapy induction and filtered by CellSieve filtration. Quantities and subtypes of CTCs & CAMLs were categorized by their expression of CK+/CD45+/CD14+ for CAMLs and CK+/CD45-/CD14- for CTCs. PFS (RECIST v1.1) and OS hazard ratios (HRs) were calculated by censored univariate & multivariate analysis at 2 years. Results: Pt median age was 51 years (range 25-92); TNBC (44%), ER/PR+ (30%), HER2+ (15%). Pts were treated with chemotherapy alone (18%), immune checkpoint inhibitor (46%), targeted (40%), hormone (8%) and unknown (5%). 38% (81/212) pts had ≥1 CTCs which correlated with significantly poorer PFS (HR = 1.9; 95%CI 1.3-2.7; p = 0.0016) and OS (HR = 2.0; 95%CI, 1.3-3.0; p = 00025), with the most significant risk at ≥8 CTCs (14% pts), PFS (HR = 3.8; 95%CI, 2.1-6.9; p < 0.0001) and OS (HR = 7.2; 95% CI, 3.4-14.9; p < 0.0001). Independently, 93% (n = 196/212) of pts had ≥1 CAML, with a threshold of >40um size (84% pts) had significantly poorer PFS (HR = 2.0; 95% CI, 1.2-3.1; p = 0.0032), but not OS (HR = 1.5; 95%CI, 0.9-2.7; p = 0.1169). However, a threshold of >125um size CAML (43% pts) also had significantly poorer PFS (HR = 1.8; 95% CI, 1.2-2.7; p = 0.0013) and OS (HR = 1.6; 95% CI, 1.0-2.5; p = 0.0233). By combining models, the best outcomes were seen in pts with 0 CTCs & 0 CAMLs (mPFS = 12.6 & mOS = 21.3), followed by 0 CTCs & ≥40um CAMLs (mPFS = 5.2 & mOS = 17.5) and 0 CTCs & ≥125um CAMLs (mPFS = 4.9 & mOS = 15.2). Poorer outcomes were seen with ≥1 CTCs (mPFS = 3.3 & mOS = 13.5) and the worst outcomes with ≥8 CTCs (mPFS = 2.5 & mOS = 4.8). Conclusions: CTCs were uncommon in mBC pts but correlated with very poor clinical outcomes. In parallel analysis, CAMLs were common with CAML size correlating with increasingly poorer outcomes. By combining CTC & CAML subtypes, mBC pts were more accurately stratified by risk of progression and death. Additional multivariate studies correlating treatment class and tumor response rates are ongoing.

BACKGROUND: Hemorrhagic risk in dural arteriovenous fistulas (dAVFs) is largely determined by venous anatomy, but the contribution of systemic cardiovascular factors and their medical therapy remains poorly defined. This study examined associations between cardiovascular risk factors and antithrombotic use and hemorrhagic presentation, angiographic obliteration, and early functional outcomes after treatment. METHODS: We analyzed 1350 adults with intracranial dAVFs from the international Consortium for Dural Arteriovenous Fistula Outcomes Research registry, which retrospectively accrued cases across 14 centers in 4 countries between 1990 and 2017. Demographics, cardiovascular comorbidities, antithrombotic use, angioarchitectural features, treatment strategies, and follow-up outcomes were collected from prospectively maintained databases. Primary end points were hemorrhagic presentation, angiographic obliteration, and 90-day functional status after treatment. Univariable and multivariable logistic regressions were performed with model-specific adjustments. RESULTS: Hemorrhage occurred in 375 patients (27.8%) and was most strongly associated with high-grade dAVF classification and male sex; antithrombotic therapy was associated with lower odds of hemorrhagic presentation. Other cardiovascular risk factors showed no independent relationship with bleeding. Angiographic obliteration was achieved in 621 of 845 patients (73.5%). Hemorrhagic onset, high dAVF grade, and surgical treatment were independently associated with angiographic obliteration, whereas smoking and embolization demonstrated only nonsignificant trends after adjustment. At 90 days, 934 patients (88.9%) were functionally independent. Baseline modified Rankin Scale score was the strongest factor associated with 90-day functional outcome, while neither cardiovascular comorbidities nor treatment modality independently influenced functional status. CONCLUSIONS: In this large multicenter dAVF cohort, hemorrhagic presentation was most strongly associated with venous angioarchitecture. Male sex and antithrombotic therapy were also independently associated with hemorrhagic presentation. Angiographic obliteration was common, particularly among surgically treated lesions, and 90-day functional outcome was most strongly associated with baseline functional status.

Abstract Aims Chronic kidney disease (CKD) is common in patients with heart failure (HF) with preserved ejection fraction (HFpEF), and its presence is associated with more severe echocardiographic abnormalities and poorer outcomes through unclear mechanisms. CKD-associated endothelial dysfunction, inflammation, and activation of profibrotic pathways could worsen pulmonary vascular disease (PVD) in HFpEF, but such relationships have not been explored. Methods Consecutively evaluated patients with HFpEF undergoing invasive haemodynamic cardiopulmonary exercise testing were stratified by baseline kidney function to characterize potential differences in pulmonary vascular loading, haemodynamics, cardiopulmonary reserve, and outcomes based upon the presence and severity of kidney dysfunction. Results Of 925 patients with HFpEF, 319 (34.5%) had estimated glomerular filtration rate (eGFR) &lt; 60 ml/min/1.73 m2. Patients with more severe kidney dysfunction were older and more likely to have diabetes, atrial fibrillation, and hypertension. At rest, reduced kidney function was associated with lower haemoglobin, higher biventricular filling pressures, and lower cardiac output, but the severity of kidney dysfunction was most conspicuously associated with worsening PVD, evidenced by increasing pulmonary arterial (PA) pressures due to marked increases in pulmonary vascular resistance (PVR) as kidney dysfunction progressed (median [IQR] 1.3 [0.86, 1.88] to 2.8 [2.0, 3.8] WU from eGFR ≥ 90 to eGFR &lt; 30, P &lt; .001), along with progressively lower PA compliance (PAC, 4.7 [3.6, 5.8] to 2.2 [1.8, 3.4] ml/mmHg from eGFR ≥ 90 to eGFR &lt; 30, P &lt; .001). With exercise, differences in the severity of PVD became even more striking, with more severe elevation in PA pressures and PVR, and lower PA compliance, leading to lower transmural left-sided distending pressures, with no difference in exertional PA wedge pressure. Patients with worse kidney dysfunction displayed the most dramatic cardiac output limitations with exercise, which along with more severe anaemia and markedly reduced O2 delivery, caused marked impairment in aerobic capacity. Worsening kidney function was associated with a striking gradient of increased risk of a composite of all-cause death and HF hospitalization [ranging from HR 2.38 (95% CI 1.01–5.59) for eGFR 60–90 to HR 16.77 (95% CI 6.65–42.28) for eGFR &lt; 30 (vs. reference eGFR ≥ 90)]. Conclusions Kidney dysfunction in patients with HFpEF is characterized by more severe PVD at rest and with exercise, leading to reduced cardiac output reserve, impaired exercise capacity, and increased risk for adverse events. Further study is warranted to better understand causal relationships between CKD and PVD, and determine whether novel therapies to improve kidney function might target these impairments to improve clinical status.

OBJECTIVE Dural arteriovenous fistulas (dAVFs) are rare cerebrovascular anomalies. Tentorial dAVFs (TDAVFs) have more aggressive features, making them prone to symptomatic presentations and hemorrhage. TDAVFs are heterogenous and require tailored surgical approaches. Presented is a multicenter analysis of TDAVF surgical outcomes. METHODS The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) consortium compiled data on dAVFs from 16 international centers from 1990 to 2021 retrospectively. Microsurgical treatment success was defined as angiographically confirmed complete obliteration of the fistula or discontinuation of cortical venous drainage (CVD) in high-grade TDAVFs. TDAVF subtypes and tailored surgical approaches were reviewed. RESULTS Of 1360 patients in CONDOR, 161 had TDAVFs and 27% (44/161) of these patients underwent surgical management, with the majority (52% [23/44]) receiving surgery as a salvage treatment following failed embolization. The mean age (SD) of this cohort was 56 (15) years, and 68% (30/44) were male. In total, 91% (40/44) of surgically treated patients presented with aggressive symptoms: 64% (28/44) presented with hemorrhage and 27% (12/44) with nonhemorrhagic neurological deficit (NHND). The median (IQR) duration from symptom onset to diagnosis was 1 (1–4) day. The median time (IQR) between diagnosis and surgery was 15 (3–80) days. Surgical approaches varied across the cohort, with the retrosigmoid being the most common (44% [18/41]), followed by the midline suboccipital (24% [10/41]) and occipital (15% [6/41]) approaches. Perioperative complications occurred in 11% (5/44) of cases, as well as permanent neurological deficits in 2% (1/44). Surgical success was achieved in 90% of patients (38/42). During the mean 3-year follow-up, 2 patients experienced a recurrence of their fistula including representation of CVD (2/38 [5%]) and 1 patient had a new NHND (1/43 [2%]). Shorter symptom duration was significantly associated with success (15.6 vs 181.5 days, p = 0.001). Primary versus salvage microsurgery showed no difference in outcomes. Both patients with recurrent fistula were effectively treated with Gamma Knife radiosurgery. CONCLUSIONS Resection is safe and durable for the treatment of TDAVF not otherwise amenable to embolization. It can achieve a high degree of success with a low rate of perioperative complications and permanent neurological deficits, benefits far exceeding the risks associated with TDAVF natural history or management with less effective modalities.

Abstract Background Approximately one-third of patients with heart failure and preserved ejection fraction (EF) (HFpEF) have exercise-induced left atrial hypertension (EILAH), characterized by normal pulmonary capillary wedge pressure (PCWP) at rest, but with pathologic PCWP elevation during exercise. It has been proposed that EILAH may represent an early stage of HFpEF that progresses to resting LA hypertension (RELAH) over time, but this has never been shown. Purpose This observational study aimed to investigate the natural history of patients with EILAH, evaluating patients who underwent multiple invasive hemodynamic evaluations over time. Methods Consecutively-evaluated patients with HFpEF and EILAH (PCWP&lt;15 mmHg at rest and ≥25 mmHg during exercise) who underwent subsequent invasive hemodynamic testing were identified. Prevalence and characteristics of transition to RELAH (PCWP≥15 mmHg at rest) were evaluated. Results Of 659 patients with EILAH, 84 underwent repeat invasive hemodynamic evaluations over a median follow-up of 1.81 (IQR 0.48-3.40) years (55 female, mean age 66 years). Of this group, 33 (39%) patients changed to RELAH and 51 (61%) remained EILAH. Patients with change to RELAH experienced greater increase in NT-proBNP (+16.6%; 95% CI: 7.1% to 26.0%, P&lt;0.001), decreased left ventricular EF (-6.1%, 95% CI: -9.7 to -2.5, P=0.001), right ventricular (RV) global longitudinal strain (-4.5%, 95% CI: -8.8 to -0.3, P=0.037), RV free wall longitudinal strain (-7.3%, 95% CI: -13.1 to -1.6, P=0.013) and worsening tricuspid regurgitation (15% vs 2%, P=0.025) compared to those with no change (Figure 1). Upon invasive hemodynamic at rest, patients with change to RELAH experienced an increase in right atrial pressure (RAP) (+4.4 mmHg, 95% CI: 2.6 to 6.1, P&lt;0.001) and mean pulmonary artery (PA) pressure (+6.6 mmHg, 95% CI: 4.2 to 9.0, P&lt;0.001) (Figure 1). At the baseline, there were no significant differences in the exercise-induced increases in PCWP, mean PAP, and RAP between the two groups from rest to peak exercise (Figure 2). However, at the final evaluation, patients with change to RELAH displayed a greater increase in PCWP, mean PAP, and RAP during exercise as compared to those who remained EILAH (Figure 2). Of characteristics at the index evaluation, history of atrial fibrillation (OR 3.73; 95% CI 1.09-12.8, P=0.036), and lower resting PA compliance (OR 0.49; 95% CI 0.24-0.99, P=0.048) were independently associated with the transition to RELAH after adjusting the duration from baseline to final examination. Conclusions Approximately 40% of patients with HFpEF that first present with EILAH to RELAH, suggesting that EILAH can be considered an earlier form of HFpEF. History of atrial fibrillation and reduced PA compliance are associated with progression to RELAH, suggesting that interventions to address atrial myopathy and pulmonary vascular disease may be effective to attenuate or prevent this transition.

Abstract Background Left atrial pressure (LAP) is clinically estimated by the occluded pulmonary artery (PA) pressure (PA wedge pressure, PAWP), which should equalize with downstream LAP. Early studies reported the potential for PAWP to exceed LAP, but the frequency and clinical significance of this finding is unclear. Purpose This study aimed to investigate the hemodynamic characteristics, physiologic determinants, and prognostic impact of patients with PAWP exceeding LAP. Method Patients who underwent right heart catheterization (RHC) for diagnosis or treatment with PAWP and simultaneous measurement of LAP were identified. Patients were divided into two groups based on differences in PAWP and LAP. Pulmonary capillary pressure (Pc) was measured using the PA occlusion technique. Pulmonary vascular resistance (PVR) was then partitioned into upstream PVRa ([mean PA pressure (PAP)-Pc]/cardiac output [CO]) and downstream PVRv ([Pc-PAWP]/CO), with each expressed as a percentage of PVR. Results 675 patients underwent RHC with transseptal puncture allowing measurement of both PAWP and LAP simultaneously. A strong correlation and agreement between PAWP and LAP were demonstrated (r=0.92, P&lt;0.001; bias +0.5 mmHg), but 310 patients (46%) displayed PAWP exceeding LAP by at least 1 mmHg (mean difference 3±2 mmHg). Patients with PAWP exceeding LAP displayed higher mean PAP (Figure 1A) and PVR calculated using LAP as the downstream pressure (PVR-LA: 2.10 [1.13-3.53] vs 3.38 [2.19-5.66] WU, P&lt;0.001). PAWP was significantly higher in patients with PAWP exceeding LAP, although there was no significant difference in LAP between the groups (Figure 1B-C). PA compliance, which does not rely on either PAWP or LAP for calculation, was significantly lower in patients with PAWP exceeding LAP (2.7 [1.8-4.0] vs 2.1 [1.5-3.0] mL/mmHg, P&lt;0.001, Figure 1D). The difference between PAWP and LAP was significantly correlated with mean PAP (r=0.32, P&lt;0.001, Figure 1E). In 63 patients where Pc could be measured, those with PAWP exceeding LAP showed a higher Pc and greater pulmonary venous (vs arterial) distribution of PVR (Figure 1F-H). Over 5.4 (IQR 1.7-10.2) years, the composite outcome of all-cause death or heart failure hospitalization occurred in 326 patients (48%). Patients with PAWP exceeding LAP had a higher risk of the composite outcome than those without (log-rank P&lt;0.001, Figure 2). Patients with PAWP exceeding LAP had 37% greater risk of composite outcome than those without (hazard ratio 1.37, 95% CI 1.09-1.73; P=0.008) after adjusting for age, sex, hemoglobin, moderate or greater mitral regurgitation, and tricuspid regurgitation, LAP, and mean PAP. Conclusions While PAWP is a robust surrogate for LAP, the former commonly exceeds the latter, and patients with PAWP exceeding LAP have more severe pulmonary vascular disease, greater capillary hypertension and venous involvement, and a higher risk for adverse outcomes.