Suppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction

Background: Soluble suppression of tumorigenicity 2 (sST2) receptor is a biomarker that is elevated in certain systemic inflammatory diseases. Comorbidity‐driven microvascular inflammation is postulated to play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology, but data on how sST2 relates to clinical characteristics or inflammatory conditions or biomarkers in HFpEF are limited. We sought to determine circulating levels and clinical correlates of sST2 in HFpEF. Methods and Results: At enrollment, patients (n=174) from the Phosphodiesterase‐5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial of sildenafil in HFpEF had sST2 levels measured. Clinical characteristics; cardiac structure and function; exercise performance; and biomarkers of neurohumoral activation, systemic inflammation and fibrosis, and myocardial necrosis were assessed in relation to sST2 levels. Median sST2 levels in male and female HFpEF patients were 36.7 ng/mL (range 30.9–49.2 ng/mL; reference range 4–31 ng/mL) and 30.8 ng/mL (range 25.3–39.3 ng/mL; reference range 2–21 ng/mL), respectively. Among HFpEF patients, higher sST2 levels were associated with the presence of diabetes mellitus; atrial fibrillation; renal dysfunction; right ventricular pressure overload and dysfunction; systemic congestion; exercise intolerance; and biomarkers of systemic inflammation and fibrosis, neurohumoral activation, and myocardial necrosis (P<0.05 for all). sST2 was not associated with left ventricular structure or left ventricular systolic or diastolic function. Conclusions: In HFpEF, sST2 levels were associated with proinflammatory comorbidities, right ventricular pressure overload and dysfunction, and systemic congestion but not with left ventricular geometry or function. These data suggest that ST2 may be a marker of systemic inflammation in HFpEF and potentially of extracardiac origin. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867

Prognosis of Transthyretin Cardiac Amyloidosis Without Heart Failure Symptoms.

BACKGROUND Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers. OBJECTIVES The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. METHODS Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. RESULTS A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002). CONCLUSIONS After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.This work was supported by grants from Instituto de Salud Carlos III (PI18/0765 and PI20/01379). Dr Gonzalez-Lopez has received speaker fees from Pfizer and Alnylam; has received consulting fees from Pfizer and Proclara; and has received research and educational support to her institution from Pfizer, BridgeBio, and Alnylam. Dr Obici has received speaker and consulting fees from Pfizer, Alnylam, and Akcea. Dr AbouEzzeddine has received research grant support from Pfizer. Dr Mussinelli has received speaker fees from Pfizer and Akcea. Dr Dispenzieri has received consulting fees from Janssen and Akcea; and has received research support from Pfizer, Alnylam, Celgene, and Takeda. Dr Perlini has received speaker and consulting fees from Pfizer, Alnylam, and Akcea. Dr Palladini has received speaker fees from Janssen-Cilag, Pfizer, and Siemens; and has participated on an advisory board for Janssen Cilag. Dr Damy has received research grants or consulting fees from Alnylam, Akcea, Pfizer, and Prothena. Dr Grogan has received research grant support and consulting fees to her institution from Alnylam, Eidos, Pfizer, and Prothena. Dr Maurer has received grant support from National Institutes of Health (R01HL139671-01, R21AG058348, and K24AG036778); has received consulting income from Pfizer, GlaxoSmithKline, Eidos, Prothena, Akcea, and Alnylam; and has received clinical trial funding to his institution from Pfizer, Prothena, Eidos, and Alnylam. Dr Garcia-Pavia has received speaker fees from Pfizer, BridgeBio, Alnylam, and Ionis; has received consulting fees from Pfizer, BridgeBio, AstraZeneca, NovoNordisk, Neuroimmune, Alnylam, Alexion, and Attralus; and has received research and educational support to his institution from Pfizer, BridgeBio, and Alnylam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

High-sensitivity C-reactive protein in heart failure with preserved ejection fraction.

BACKGROUND:Microvascular inflammation may contribute to the pathogenesis of both heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH). We investigated whether the inflammation biomarker C-reactive protein (CRP) was associated with clinical characteristics, disease severity or PH in HFpEF. METHODS:Patients in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart failure (RELAX) trial had baseline high-sensitivity CRP levels measured (n = 214). Clinical characteristics, exercise performance, echocardiographic variables and biomarkers of neurohumoral activation, fibrosis and myocardial necrosis were assessed. Patients with normal (≤3mg/L) versus high (>3mg/L) CRP levels were compared. RESULTS:The median CRP level was 3.69mg/L. CRP was elevated in 57% of patients. High CRP levels were associated with younger age, higher body mass index (BMI), chronic obstructive pulmonary disease (COPD), lower peak oxygen consumption and higher endothelin-1 and aldosterone levels. CRP increased progressively with the number of comorbidities (0.7mg/L per increment in comorbidity number, P = 0.02). Adjusting for age, BMI and statin use, high CRP levels were additionally associated with atrial fibrillation, right ventricular dysfunction, and higher N-terminal pro-B-type natriuretic peptide levels (P<0.05 for all). CRP was not associated with PH or left ventricular function. CRP did not identify responders to sildenafil(P-value for interaction 0.13). CONCLUSIONS:In HFpEF, high CRP is associated with greater comorbidity burden and some markers of disease severity but CRP was normal in 40% of patients. These findings support the presence of comorbidity-driven systemic inflammation in HFpEF but also the need to study other biomarkers which may better reflect the presence of systemic inflammation

Evaluation of novel metrics of symptom relief in acute heart failure: the worst symptom score

Objective: To characterize a novel "worst"-symptom visual analogue scale (WS-VAS) versus the traditional dyspnea visual analogue scale (DVAS) in an acute heart failure (AHF) trial.Background: AFT trials assess symptom relief as a pivotal endpoint with the use of dyspnea scores. However, many AHF patients' worst presenting symptom (WS) may not be dyspnea. We hypothesized that a WS VAS may reflect clinical improvement better than DVAS in AHF.Methods and Results: AHF patients (n = 232) enrolled in the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) Trial indicated their WS at enrollment and completed DVAS and WS VAS at enrollment and 24, 48, and 72 hours. Dyspnea was the WS in 61%, body swelling in 29%, and fatigue in 10% of patients. Clinical characteristics differed by WS. In all patients, DVAS scores were higher (less severe symptoms) than WS-VAS and the change in WS-VAS over 72 hours was greater than the change in DVAS (P < .001). Changes in DVAS were smaller in patients with body swelling and fatigue than in patients with dyspnea as their WS (P = .002), whereas changes in the WS-VAS were similar regardless of patients' WS. Neither score, nor its change, was associated with available decongestion markers (change in N-terminal pro B-type natriuretic peptide, weight or cumulative 72-hour urine volume).Conclusions: Many AHF patients have symptoms other than dyspnea as their most bothersome symptom. The WS-VAS better reflects symptom improvement across the spectrum of AHF phenotypes. Symptom relief and decongestion were not correlated in this AHF study

Impact of Arrhythmias on Hospitalizations in Patients With Cardiac Amyloidosis

Cardiac involvement in amyloidosis is associated with a poor prognosis. Data on the burden of arrhythmias in patients with cardiac amyloidosis (CA) during hospitalization are lacking. We identified the burden of arrhythmias using the National Inpatient Sample (NIS) database from January 2016 to December 2017. We compared patient characteristics, outcomes, and hospitalization costs between CA patients with and without documented arrhythmias. Out of 5,585 hospital admissions for CA, 2,020 (36.1%) had concurrent arrhythmias. Propensity-score matching for age, sex, income, and co-morbidities was performed with 1,405 CA patients with arrhythmias and 1,405 patients without. The primary outcome of all-cause mortality was significantly higher in CA patients with arrhythmia than without(13.9% vs 5.3%, p-value \u3c0.001). Atrial fibrillation (AF) was the most common (72.2%) arrhythmia in CA patients with concurrent arrhythmia. The secondary outcomes of AF-related mortality (11.95% vs 9.16%, p-value = 0.02) and acute and acute on chronic as heart failure (HF) exacerbation (32.38% vs 24.91%, p-value \u3c0.0001) were significantly higher in CA and concurrent arrhythmia compared with CA patients without. The total length of hospital stay (6[3 to 12] vs 5[3 to 10], p-value \u3c0.001) and cost of hospitalization were ($15,086[7,813 to 30,373] vs$ 12,219[6,865 to 23,997], p-value = 0.001) were significantly greater among CA with arrhythmia compared with those without. These data suggest that the presence of arrhythmias in CA patients during hospital admission is associated with a poorer prognosis and may reflect patients with a higher risk of HF exacerbation and mortality

Palliative Medicine Consultation for Preparedness Planning in Patients Receiving Left Ventricular Assist Devices as Destination Therapy

OBJECTIVE: To assess the benefit of proactive palliative medicine consultation for delineation of goals of care and quality-of-life preferences before implantation of left ventricular assist devices as destination therapy (DT)