Aims Cardiac amyloidosis typically manifests as heart failure with preserved left ventricular function due to extracellular plaques comprising aggregated TTR. Despite recent success in halting disease progression with a TTR stabilizer and encouraging preliminary findings with TTR silencers, these agents are not targeting preexisting plaques. Herein, we report the development of a novel monoclonal antibody capable of attenuating experimental cardiac amyloidosis. Methods and results We generated an IgG1 monoclonal antibody against aggregated TTR that immunoprecipitated the protein in the sera of patients with wild-type ATTR (wtATTR) and robustly stained cardiac plaques from patients. The antibody was shown to facilitate aggregated-TTR uptake by various myeloid cells and to protect cardiomyocytes from TTR-inducible toxicity. In a novel in vivo model of wtATTR amyloidosis, the antibody enhanced the disappearance of the pyrophosphate signals attesting for a rapid amyloid deposit removal and degradation and also exhibited improved echocardiographic measures of cardiac performance. Importantly, a capture ELISA developed based on the antibody exhibited higher levels of aggregated TTR in the sera of wtATTR amyloidosis patients as compared to control patients with heart failure suggesting a potential applicability in diagnosis and pharmacodynamic guidance of dosing. Conclusion We developed a proprietary antibody targeting aggregated TTR that exhibits beneficial effects in a novel experimental wtATTR model and also possesses a potential diagnostic utility. The antibody could potentially be tested as a disease modifying agent in ATTR amyloidosis.

Aim Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) with preserved left ventricular ejection fraction (LVEF), typically presenting as restrictive cardiomyopathy. The potential co-existence of ATTR-CA with systolic heart failure has not been studied. The aim of this study is to describe the prevalence of ATTR-CA and its clinical characteristics in HF patients with reduced LVEF. Methods Patients with an unexplained cause of LV systolic dysfunction were screened for ATTR-CA by a 99mTc-PYP planar scintigraphy. Patients in whom presence of ≥ 2 uptake was confirmed by SPECT imaging were included. Their clinical, laboratory and echocardiographic data were collected. Results Out of 75 patients (mean age 65±12 years, LVEF 35.8±7.9%) included in this study, 7 (9.3%) patients (mean age 75±6 years, LVEF 32.0±8.3%) had ATTR-CA. Patients with ATTR-CA were more symptomatic at diagnosis (NYHA FC 3–4 (86% vs 35% (p = 0.03)) and had a more severe clinical course evident by recurrent hospitalizations for HF, and a need for intravenous diuretic treatment (p = 0.04 and p<0.01, respectively) at follow-up, compared with patients with no ATTR-CA. Patients with ATTR-CA had similar LVEF but a clear trend for larger LV mass index (157.1±60.6 g/m2 vs. 121.0±39.5 g/m2, p = 0.07) and a larger proportions of ATTR-CA patients had IVS thickness >13 mm (57.1% vs 13.1%, p = 0.02) as compared to HF patients with no ATTR-CA. Conclusion In our study, a meaningful percentage of patients with unexplained LV dysfunction had a co-existing ATTR-CA indicating that the clinical heterogeneity of ATTR-CA is much broader than previously thought.

Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a membrane receptor in myeloid cells that mediates cellular phagocytosis and inflammation. TREM2 and its soluble extracellular domain are clearly implicated in neuroinflammation and neurodegeneration. sTREM2 is also expressed in atherosclerotic macrophages. We hypothesized that sTREM2 would predict cardiovascular mortality in patients with established coronary atherosclerosis (CAD). Consecutive patients undergoing coronary angiography with the establishment of the diagnosis of CAD (n = 230) and without CAD (n = 53) were tested for their baseline serum sTREM2 levels. All patients were followed up for 84 months or until death occurred. sTREM2 correlated with age; however, no association was found between sTREM2 and the number of atherosclerotic vessels involved (p = 0.642). After 84 months of follow-up, 68 out of the 230 CAD patients had died. After adjusting for age and other risk factors, the adjusted hazard ratio for the highest quartile of sTREM2 was 2.37 (95% confidence interval 1.17–4.83) for death. In patients with established CAD, serum sTREM2 appears to predict cardiovascular death as a potential surrogate for plaque rupture. TREM2 and its soluble extracellular form might be implicated in the fate of the atherosclerotic plaque, but corroboration within larger studies is needed.

Introduction: Right heart catheterization (RHC) is a diagnostic procedure, the main purpose of which is to diagnose pulmonary hypertension and investigate its etiology and treatability. In addition to measuring blood pressure in heart chambers, it includes estimating cardiac output (CO) and calculation of pulmonary vascular resistance (PVR) derived from the CO. There are two common methods to evaluate the CO—the indirect Fick method and the thermodilution method. Depending on the clinical conditions, either of the two may be considered better. Several studies have showed that, in most cases, there is no difference between measurements rendered by the two methods. Other studies have raised suspicion of a discrepancy between the two methods in a substantial number of patients. A clear opinion on this matter is missing. Aim: To evaluate the agreement between the values of the CO and PVR found by the thermodilution and indirect Fick methods. Methods: We retrospectively included patients that underwent RHC in Kaplan Medical Center during the last two years with a measurement of the CO using both the thermodilution and the indirect Fick methods. The measurements obtained upon RHC and the clinical data of the patients were collected. The values of the CO and PVR measured or calculated using the two methods were compared for each patient. Results: We included 55 patients that met the inclusion criteria in this study. The mean CO measured by the thermodilution method was 4.94 ± 1.17 L/min and the mean CO measured by the indirect Fick method was 5.82 ± 1.97 L/min. The mean PVR calculated using the thermodilution method was 3.33 ± 3.04 Woods’ units (WU) and the mean PVR calculated using the indirect Fick method was 2.71 ± 2.76 WU. Among the patients with normal mPAP, there was a strong and statistically significant correlation between the PVR values calculated by the two methods (Peasron’s R2 = 0.78, p-value = 0.004), while among the patients with elevated mPAP, the correlation between the PVR values calculated by the two methods was not statistically significant. Conclusion: The findings of this small study demonstrate that, in a proportion of patients, the indirect Fick method and thermodilution method classify the PVR value differently. In our experience, it seems that, in these patients, the indirect Fick method misclassified patients with a pathological finding as normal. We, therefore, recommend that upon performing RHC, at least in patients with mPAP > 25 mmHg, both the thermodilution and indirect Fick methods be performed and, whenever they disagree, the values obtained from the thermodilution method should be preferred.