AbouEzzeddine, Omar F.

Abstract Aims Patient-reported quality of life (QOL) is a highly prognostic and clinically relevant endpoint in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The relationships between QOL and different markers of HF severity remain unclear, particularly as they relate to functional capacity and directly measured activity levels. We hypothesized that QOL would demonstrate a stronger relationship with measures of exercise capacity and adiposity compared to other disease measures. Methods and results This is a secondary analysis of the National Heart, Lung, and Blood Institute-sponsored RELAX, NEAT-HFpEF and INDIE-HFpEF trials to determine the relationships between QOL (assessed by the Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire) and different domains reflecting HF severity, including maximal aerobic capacity (peak oxygen consumption), submaximal exercise capacity (6-min walk distance), volume of daily activity (accelerometry), physician-estimated functional class, resting echocardiography, and plasma natriuretic peptide levels. A total of 408 unique patients with chronic HFpEF were split into tertiles of QOL scores defined as QOLworst, QOLintermediate, QOLbest. The QOLworst HFpEF group was youngest, with a higher body mass index, greater prevalence of class II obesity and diabetes, and the lowest N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. After adjustment for age, sex and body mass index, poorer QOL was associated with worse physical capacity and activity levels, assessed by peak oxygen consumption, 6-min walk distance and actigraphy, but was not associated with NT-proBNP or indices from resting echocardiography. QOL was similarly reduced in patients with and without prior HF hospitalization. Conclusions Quality of life in HFpEF is poorest in patients who are young, obese and have diabetes, and is more robustly tied to measures reflecting functional capacity and daily activity levels rather than elevations in NT-proBNP or prior HF hospitalization. These findings have major implications for the understanding of QOL in HFpEF and for the design of future clinical trials targeting symptom improvement in HFpEF. Clinical Trial Registration: RELAX, NCT00763867; NEAT-HFpEF, NCT02053493; INDIE-HFpEF, NCT02742129.

The transthyretin (TTR) and immunoglobulin light chain proteins do not exist in isolation in cardiac amyloid (CA) plaques. Laser microdissection followed by mass spectrometry-based proteomic (LMD-MS) typing techniques can identify hundreds of co-deposited proteins in the "nano-environment" of amyloid deposits. Some, such as the "amyloid signature" proteins (SAP, APOE, APOA4, vitronectin, clusterin), are specific for amyloid plaques across different tissues and amyloid types. However, many of the remaining proteins are also abundant in the serum or normal tissues making it difficult to discern if they are unique to the amyloid plaque or part of the normal tissue background. We included 288 patients/samples with TTR CA (of which 53 were mutated) diagnosed by endomyocardial biopsy and 5 normal control samples obtained from 3 patients during autopsy. At the time of the meeting updated analyses including 168 cardiac light chain amyloid patients and 15 controls from patients with restrictive and hypertensive cardiomyopathy will be presented. Normalized spectral counts were used as a semi-quantitative measure of abundance. Proteins were considered part of the proteome if their abundance in the amyloid plaque was increased by 1.5-fold compared to normal controls (FDR p<0.05). Of 2240 unique proteins identified across all samples, 42 were differentially expressed in amyloid plaques. These included a) signature proteins: SAP, APOE, APOA4, vitronectin, clusterin; b) serum proteins: albumin, b2-glycoprotein, 7 complement pathway proteins; c) matrix proteins: 2 collagen isoforms, fibulin 1, decorin, PCOLCE2, TIMP3; d) cytosketal and contractile proteins: 2 actin isoforms, MYL2, 8 myosin isoforms, 3 ankyrin isofroms, desmin; and "other" proteins: serpine2, MAGE-like protein-2, pleiotrophin, AMBP, SRPX and QSOX1). The signature and cytoskeletal proteins were the most abundant overall, however, proteins that were most increased compared to normal included (log2 fold change in parentheses): fibulin (24.5), PCOLCE2 (23.5), b2-glycoprotein (23.5), factor H related peptide-2 (24.2), serpine2 (24.7), mage-like protein-2 (22.8), pleiotrophin (23.8), QSOX1 (22.9), SRPX (23.5). B2 glycoprotein was more abundant in wild type TTR samples(p=0.003). APOE (p=0.002), fibulin (p=0.008) and serpine2 (p<0.0001) were more abundant in UK stage (Gilmore JD et al, Eur Heart J 2018) 2/3 patients. Unsupervised hierarchical clustering of patients by normalized protein abundance revealed two major distinct patterns of co-deposited proteins (figure). Patients with high levels of contractility proteins (myosin isoforms, desmin, actins) were characterized by low levels of most other proteins (clusters on the left). Most complement proteins co-deposited along with higher levels of signature proteins (clusters on the right). When comparing clinical and laboratory characteristics between those 2 groups of patients only cardiac strain was found to be significantly higher (worse) in patients with lower levels of contractility proteins (p=0.01). Our data shows that the TTR CA proteome includes signature, serum and cardiac tissue proteins with variable expression according to TTR mutation status and cardiac functional status, which could inform mechanisms of disease pathogenesis. Comparison with diseased controls may further clarify if this proteomic pattern is specific to CA. Figure Disclosures Dasari: The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding.

Background: The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O 2 consumption [MVO 2 ]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O 2 extraction. Lastly, we assessed whether coupling of MVO 2 to EW (mechanical efficiency) was impaired in HFpEF. Methods and Results: In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11 C-acetate positron emission tomography assessing MVO 2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO 2 , and MBF. With dobutamine, LV EW, MVO 2 , and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O 2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. Conclusions: In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O 2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O 2 supply relative to demand, and is associated with reserve dysfunction.

Abstract Introduction: Prognosis of AL amyloidosis has improved in recent years; however for many patients prognosis remains poor. We aimed to define patient-, disease- and treatment characteristics which are associated with long-term survival. Method: A retrospective chart review of all patients with biopsy-proven systemic AL amyloidosis, who were seen within 90 days of the confirmed diagnosis. Long-term survival was defined as 5-year and 10-year survival from the time of diagnosis. For 5-year survival we selected patients seen between January 1, 2000 and December 31, 2012 (allowing a minimum of 5-year follow-up, n=1331) and for 10-year survival we screened patients seen between January 1, 2000 and December 31, 2007 (allowing a minimum of 10-year follow-up; n=779). Treatment allocation was defined as the first regimen given, irrespective of subsequent treatment modifications. Results: Of the screening population, 498 patients survived ≥5 years from diagnosis (37% of the 5-year screening cohort) and 168 patients survived 10 years or more (22% of the 10-year screening cohort). Five-year survivors and 10-year survivors as compared to their counterparts were (Table): younger, higher proportion of women, more likely to have single organ involvement, less heart/liver/nerve involvement and more kidney involvement. Long-term survivors also had lower bone marrow plasma cell percentage at the time of diagnosis and lower tumor burden measured by the difference between involved to uninvolved light chain (dFLC). Similarly, long-term survivors had lower Mayo stages and higher systolic blood pressure. No difference in light chain isotype was observed between long-term survivors to long term non-survivors. Long-term survivors were less likely to be seen within 30 days of diagnosis compared to their counterparts (52% among 5-year survivors vs 67% among 5-year non-survivor; P<0.001). FISH abnormalities (data available for 555/1331 patients, 42%) were comparable between groups with regard to t(11;14) (50% among 5-year survival compared to 50% among 5-year non-survivors; P=0.93) and 13q abnormalities (34% vs 36%, respectively; P=0.53). However, trisomies were less frequently encountered in the 5-year survivor group (20% vs 29%, respectively; P=0.01), and far less common among 10-year survivors (11% vs 26%, respectively; P=0.04). Autologous stem cell transplantation (ASCT) was more likely to be associated with long-term survival. Of all patients who underwent ASCT, 74% survived more than 5 years and 49% survived more than 10 years. In comparison, among the standard-intensity therapies, 5-year survival rates for melphalan-dexamethasone, bortezomib-based regimens, immunomodulatory drug-based regimens and single agent dexamethasone/ melphalan-prednisone were 29%, 28%, 30% and 10%, respectively. The corresponding 10-year survival rates were 15%, 20%, 20% and 5%, respectively. Conclusions: Long-term AL survivors have distinct favorable baseline characteristics (including those introduced by referral bias) and ASCT as their initial therapy. Identification of these patients, especially the Mayo 2004 stage III and the Mayo 2012 stage III-IV patients who unexpectedly survived 10 years, will allow for further study and insights. Disclosures Gertz: Teva: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; janssen: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Summary Improvement in survival in Light chain (AL) amyloidosis has been seen over recent decades, enabling more patients to achieve long‐term survival. Patients with AL amyloidosis who survived ≥10 years from time of diagnosis ( n = 186) were the subject of this study. Ten‐year survivors represented 22% of the total population. These patients were characterized by favourable patient, organ and plasma cell features. Of note, trisomies were less common among 10‐year survivors compared to those who did not survive to 10 years. All‐time best haematological response was complete response in 67%, very good partial response in 30%, partial response in 2% and no response in 1%, with 11% having received a consolidative strategy for inadequate response to first line therapy. The overall organ response rate to first‐line therapy was 76%, which increased to 86% when considering subsequent line(s) of therapy. Forty‐seven percent of the 10‐year survivors did not require a second‐line therapy. The median treatment‐free survival (TFS) among the 10‐year survivors was 10·5 years (interquartile range 7·4‐12·2). On multivariate analysis independent predictors for TFS were the achievement of complete haematological response and lack of cardiac involvement. Long‐term survivors are increasingly seen in AL amyloidosis and present distinct patient, organ and clonal disease features.

Background We sought to study the prevalence of high‐sensitivity troponin and its association with cardiac structure and outcomes in ambulatory and hospitalized patients with heart failure with a preserved ejection fraction ( HF p EF ). Methods and Results A post hoc analysis utilized data from HF p EF patients: DOSE (Diuretic Optimization Strategies Evaluation) and CARRESS ‐ HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) enrolled patients hospitalized with acute HF p EF , and RELAX (Phosphodiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) enrolled ambulatory patients with HF p EF . High‐sensitivity troponin I (hs‐TnI) was measured in hospitalized patients at baseline, at 72 to 96 hours, on day 7, and on day 60. In ambulatory patients hs‐TnI was measured at baseline and at week 24. In the ambulatory cohort, correlations between hs‐TnI and cardiac structure and function were assessed. The association between hs‐TnI and a 60‐day composite of emergency room visits, readmissions, and death was assessed for hospitalized patients using multivariable Cox proportional hazard models. The study population included 139 hospitalized and 212 ambulatory patients with HF p EF and hs‐TnI measured at baseline. The median (25th, 75th percentiles) baseline troponin was 17.6 (11.1, 41.0) ng/L in hospitalized patients and 9.5 (5.3, 19.7) ng/L in ambulatory patients ( P <0.001). The prevalence of elevated hs‐TnI (>99% percentile upper reference limit was 86% in hospitalized patients and 53% among ambulatory patients, with stable elevation in ambulatory patients during follow‐up. HF p EF patients with a hs‐TnI above the median were older with worse left ventricular hypertrophy and diastolic dysfunction. Continuously valued hs‐TnI (per doubling) was associated with increased risk of composite end point (adjusted hazard ratio 1.20, 95% confidence interval 1.00‐1.43; P =0.042). Conclusions Hs‐TnI is commonly elevated among both hospitalized and ambulatory patients with HF p EF . Increased hs‐TnI levels are associated with worse cardiac structure and increased risk of adverse events.

AbstractSoluble ST2 (sST2) is a novel biomarker of inflammation and fibrosis. Elevated sST2 levels (≥35 ng/mL) are associated with worse outcomes in patients with heart failure (HF). There are sparse data regarding the significance of sST2 levels after heart transplantation (HTx). The study aims were to evaluate trends in soluble ST2 levels after the resolution of HF status with HTx and association between post‐HTx sST2 levels and outcomes. Plasma sST2 levels were measured at baseline (median [IQR] of 118 days pre‐HTx) and 12 months post‐HTx in 62 subjects who were stratified into two groups by post‐HTx sST2 levels < or ≥35 ng/mL: “Group 1” or “Group 2,” respectively. Plasma sST2 levels were elevated in 58% of patients pre‐HTx and in 50% of patients post‐HTx. There was no association between elevated sST2 levels before and after HTx, and no significant differences in baseline characteristics between Group 1 and Group 2 patients. Group 2 as compared to Group 1 HTx recipients had significantly higher incidence of antibody‐mediated rejection (AMR) for the entire post‐transplant follow‐up period (32% vs 4%, P = 0.006). There was no association between post‐HTx sST2 level status and other post‐HTx outcomes including survival. In conclusion, elevated plasma sST2 levels after HTx are associated with increased risk for AMR.