Citations

Abstract Aims The pathophysiology of tricuspid regurgitation (TR) during exercise in heart failure with preserved ejection fraction (HFpEF) is not well understood. Methods and results We investigated dynamic changes in TR severity during exercise in patients with HFpEF and associated relationships with haemodynamics, cardiopulmonary reserve, and prognosis using invasive haemodynamic exercise testing with simultaneous echocardiography and expired gas analysis. Among 169 patients with HFpEF (91 no TR, 44 mild TR, 34 ≥ moderate TR), older age and atrial fibrillation were more common in patients with greater TR severity. Right heart remodelling and dysfunction were more frequently observed with greater TR severity, particularly in the right atrium, along with stepwise increases in right atrial (RA) pressure and interventricular septal flattening, and decreases in cardiac output (CO). During exercise, TR severity frequently worsened, and over half of the patients with moderate TR at rest displayed severe TR during exercise, accompanied by profound RA dilatation, reduced RA reservoir strain, increased septal flattening, and more severely impaired CO reserve. Abnormalities in tricuspid annular motion and ventricular interaction were amplified by exercise with greater TR, but exercise pulmonary vascular pressures did not differ across groups. Patients with ≥ moderate TR during exercise displayed higher event rates (hazard ratio 2.85, 95% confidence interval 1.18–6.85), but patients with mild TR had similar prognosis as those without TR in adjusted models. Conclusions Tricuspid regurgitation in HFpEF is related to advanced RA myopathy and often worsens during exercise leading to dynamic right-sided heart failure, exaggerated ventricular interaction, impaired CO reserve, and increased risk for adverse outcomes. These data emphasize the clinical importance of exercise evaluation and call for further study of novel treatments in those with significant resting and provocable TR.

Subjective and objective limitations to exercise and activity are hallmarks of heart failure (HF), regardless of underlying ejection fraction (EF). These limitations relate to cardiovascular abnormalities involving the systolic and diastolic properties of the heart, venous, and arterial vasculature, as well as noncardiovascular abnormalities, including impairments in pulmonary function, autonomic regulation, anemia, metabolism, and changes in mitochondria and skeletal muscle. The contribution of these abnormalities varies between patients with HF with preserved EF and those with HF with reduced EF, but, even within each HF subtype, there is substantial individual patient pathophysiologic variability, which suggests a potentially important role for phenotyping based on exercise reserve responses to individualize treatment. In this article, we review the current understanding of exercise reserve limitation with a focus on specific organ systems involved, both in patients with HF with preserved EF and HF with reduced EF, and how these interact to lead to symptoms of exercise intolerance and objective limitations in submaximal and peak aerobic capacity across the spectrum of HF.

Abstract Aims While intentional weight loss achieved through cardiometabolic medications has been associated with robust salutary effects in heart failure (HF) with preserved ejection fraction (HFpEF), the clinical significance of unintentional weight loss in this setting remains unclear. Methods and results This retrospective cohort study included 434 overweight or obese patients with invasively proven HFpEF (67 ± 11 years, 236 female), without weight-reducing therapies or known malignancy, who underwent invasive hemodynamic cardiopulmonary testing and long-term clinical follow-up. The annualized weight change from index to final evaluation for the tertiles was: −21.1 to −1.8 kg/year (tertile 1); −1.8 to 0 kg/year (tertile 2); and 0 to +17.0 kg/year (tertile 3). Patients in tertile 1 had subtle abnormalities in ventilatory control at baseline, but there were no other significant differences between groups across a vast array of haemodynamic and metabolic parameters, both at rest and during exercise. Baseline weight was directly correlated with right and left heart filling pressures (r = 0.23–0.34, p < 0.001), but annualized weight change showed no correlation with any baseline haemodynamic measurements (all p > 0.05). Over a median follow-up of 4.7 years (interquartile range 2.3–6.5), patients in tertile 1 had higher risk of all-cause death (hazard ratio [HR] 3.36, 95% confidence interval [CI] 1.77–6.39, p < 0.001), all-cause death or HF hospitalization (HR 2.49, 95% CI 1.53–4.04, p < 0.001) and cardiac death or HF hospitalization (HR 2.28, 95% CI 1.28–4.07, p = 0.005) compared with those in tertile 2 or 3. These findings were consistent after multivariable adjustment. Conclusions Unintentional weight loss is associated with worse prognosis in patients with HFpEF and overweight or obesity, even as haemodynamics, exercise capacity, and gas exchange are not different from patients with stable or increasing weight. These data underline important and fundamental differences between therapeutic and unintended weight loss in HFpEF.

Abstract Aims Oxygen consumption at peak exercise is widely used to assess functional impairment in heart failure with preserved ejection fraction (HFpEF), but few patients exercise to this intensity in daily living. Alternative metrics that quantify submaximal fitness may provide more patient-centred evaluations, but the pathophysiology of submaximal exercise intolerance in HFpEF is unexplored. Methods and results Patients with HFpEF underwent invasive haemodynamic cardiopulmonary exercise testing with blood lactate measurement during exercise to volitional fatigue. Lactate threshold (LT) was defined as the exercise workload at which arterial lactate exceeded >2.0 mmol/L, taken as a measure of submaximal fitness. Of patients with HFpEF (n = 286), 194 (68%) reached LT at a workload of 40 W or less (LT ≤40 W), while 92 (32%) reached a workload exceeding 40 W at LT (LT >40 W). As compared to LT >40 W, patients with LT ≤40 W were more likely to be female, anaemic, and had greater pulmonary vascular disease (all p < 0.01). During 20 W exercise, participants with LT ≤40 W had higher pulmonary artery pressure, biventricular filling pressures, minute ventilation and respiratory drive, higher perceived dyspnoea and fatigue ratings, greater arterial–venous oxygen content difference, despite similar cardiac output and oxygen delivery. At peak exercise, most of these differences were no longer apparent. Findings were replicated using non-invasively-measured workload at ventilatory threshold. Conclusions Two-thirds of patients with HFpEF reach LT at workloads typical of activities of daily living. Patients with HFpEF and impaired submaximal fitness are more likely to be female, have greater pulmonary vascular disease and anaemia severity, and display greater haemodynamic, symptomatic, and ventilatory control abnormalities during low-level exercise, which are not apparent at maximal exertion. These findings have therapeutic implications and suggest a potentially important role for wider evaluation of submaximal fitness in addition to peak aerobic capacity.

Background Given the low haemorrhagic risk of intracranial low-grade dural arteriovenous fistulas (dAVFs), the benefits of routine intervention remain controversial. This study compares patient outcomes treated with stereotactic radiosurgery (SRS) versus conservative management. Method Multicentre retrospective analysis of the Consortium for Dural Arteriovenous Fistula Outcomes Research and the International Radiosurgery Research Foundation data. Inclusion criteria were (1) intracranial low-grade dAVF diagnosed by catheter-based angiography, (2) no prior dAVF-related haemorrhage and (3) management with upfront SRS (intervention group) or conservative management (observation group). The primary outcome was symptomatic improvement. Secondary outcomes included dAVF obliteration, up-conversion, haemorrhage, improvement and favourable modified Rankin Scale (mRS) at follow-up. Results 304 patients with a mean age of 56 years (SD 13.5) and a follow-up of 46.7 months (SD 45.5) were included. 135 (44.4%) were managed conservatively and 169 (55.6%) had upfront SRS. Compared with the observation group, symptomatic and mRS Score improvement (≥1-point decrease in baseline score) was more likely in the intervention group (95.1% vs 58.5%; OR=13.75 (5.61–33.69) and 37.0% vs 24.0%; OR=1.85 (1.09–3.15), respectively). These findings remained significant after multiple imputation and propensity score matching. Remaining outcomes were similar between groups. The all-cause mortality rate was 5.4% (n=16), unrelated to the dAVF or treatment. Five (3.0%) SRS-related complications were reported and resolved during the follow-up period. Conclusions SRS was associated with increased symptomatic and mRS Score improvement for low-grade dAVFs compared with conservative management. SRS had a low complication risk and did not appear to alter dAVF obliteration or haemorrhage. Future prospective trials on SRS as a first-line intervention for symptomatic low-grade dAVFs should be considered.

e15045 Background: Increased cancer cell mitosis in tumor tissue is widely regarded as an indicator of aggressive disease, a predictor of shorter survival, and an indicator of response to specific anthracycline based chemotherapies. Circulating tumor cells (CTCs) are cancer cells that detach from primary tumors, enter the bloodstream, and seed metastatic sites, which in patients (pts) with metastatic breast cancer (mBC) are also predictors of poor prognosis and reduced therapy response. Furthermore, small preliminary studies have identified a specific subtype of mitotic CTCs that appears to correlate with poor survival rates compared to CTC detection alone. However, larger studies have yet to be conducted to validate the clinical utility of mitotic CTCs. In this large multi-institutional prospective study, we isolated CTCs from the blood of n = 155 mBC pts to subtype mitotic CTCs to assess progression-free survival (PFS) and overall survival (OS) over 2 years. Methods: Peripheral blood samples (7.5ml) were prospectively collected from n = 155 mBC pts progressing on systemic therapies and prior to new systemic therapy induction (i.e., chemotherapy n = 90, hormone therapy n = 13, immunotherapy n = 51, targeted therapy n = 62). Samples were processed using CellSieve microfilters to isolate CTCs via size exclusion and fluorescently stained for CD45, Cytokeratin, and DAPI. CTCs were imaged, enumerated, and subtyped based on the presence of ≥1 mitotic event, using established visual indicators. PFS and OS were assessed over 2 years by censored univariate and multivariate analyses. Results: CTCs were detected in ~45% (n = 70/155) of pts, while mitotic CTCs were identified in a subset of this group, ~23% (n = 35/155). The presence of any CTC was associated with poor outcomes (PFS HR = 2.16, 95%CI = 1.4-3.2, p = 0.0002 and OS: HR = 2.51, 95%CI = 1.5-4.0, p = 0.0002). The presence of mitotic CTCs correlated with significantly poorer outcomes (PFS: HR = 5.6, 95%CI = 3.1-10.2, p < 0.0001 and OS: HR = 7.3, 95%CI = 3.7-14.5, p < 0.0001). Overall, pts with no CTCs had a median PFS (mPFS) of 7 months and median OS (mOS) of 24 months, pts with non-mitotic CTCs had a mPFS of 6 months and mOS of 15 months; pts with both CTCs and mitotic CTCs had a mPFS of 3 months and mOS of 5 months. Notably, 97% of pts with a mitotic CTC progressed within 6 months, regardless of systemic therapy type. Interestingly at 2 years, a sole non-progressive pt with a mitotic CTC was receiving alpelisib (a specialized PI3KCA inhibitor). Conclusions: Overall, the detection of CTCs indicated poor outcomes in pts, with mitotic CTCs correlating with significantly more aggressive disease and further reduced survival rates regardless of systemic therapy type. This study highlights the need for larger, more comprehensive studies to expand upon and validate these findings.

Abstract Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P &lt; 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.

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.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261