A novel monoclonal antibody targeting aggregated transthyretin facilitates its removal and functional recovery in an experimental model.

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.

The Association Between Longitudinal Strain at Rest and Stress and Outcome in Asymptomatic Patients With Moderate and Severe Aortic Stenosis.

BACKGROUND: Calcific aortic stenosis (AS) is a progressive disease, and once moderate AS is present, the likelihood of symptom onset within 5 years is significant. The aim of this study was to determine the incremental value of global longitudinal strain (GLS) and basal longitudinal strain (BLS) at rest and during exercise on outcomes among asymptomatic patients' with moderate and severe AS. METHODS: Seventy-five patients with isolated, asymptomatic AS and preserved left ventricular function were retrospectively enrolled and underwent symptom-limited exercise echocardiography. Clinical and echocardiographic data, including GLS and BLS at rest and during exercise, were assessed. Occurrence of AS-related cardiovascular events was recorded. RESULTS: The mean age was 71 ± 10 years, and 63% were men. The mean aortic valve gradient was 30 ± 11 mm Hg, and the mean aortic valve area was 0.98 ± 0.21 cm2. Resting GLS and BLS were -16.5 ± 4% and -16.9 ± 3.6%, respectively. Exercise stress test results were positive in 27 patients (36%). Mean exercise GLS was -17.8 ± 3.5%, and mean exercise BLS was -17.9 ± 4%. During mean follow-up of 34.5 ± 3.5 months, cardiovascular events were observed in 45 patients. In multivariate analysis, aortic valve mean gradient (HR, 1.073; 95% CI, 1.032-1.115; P < .001) and peak exercise BLS (HR, 1.177; 95% CI, 1.07-1.295; P = .001) were associated with cardiac events during follow-up. CONCLUSIONS: Reduced exercise BLS is associated with future cardiovascular events in patients' with asymptomatic AS, independently of clinical factors and conventional echocardiographic parameters. Detection of postexercise myocardial dysfunction in patients with asymptomatic AS with preserved left ventricular function can aid in risk assessment of these patients.

Circulating progenitor and apoptotic progenitor cells in patients with aortic regurgitation.

BACKGROUND: Endothelial progenitor cells (EPCs) have a role in the repair of endothelial surfaces after injury. Reduced numbers of EPCs are related to endothelial dysfunction and adverse clinical events, suggesting that endothelial injury in the absence of sufficient repair by circulating EPCs promotes the progression of vascular disease or valvular disorder. The aim of the present study was to assess the number and role of EPCs in patients with aortic valve regurgitation (AR). METHODS AND RESULTS: We assessed the number of EPCs and apoptotic EPCs in 31 patients with significant AR and compared them with 30 patients who had similar risk factors and no valvular disease. The numbers of EPCs and apoptotic EPCs were assessed by flow cytometry. The 2 groups had similar clinical characteristics. Patients with AR had fewer circulating EPCs and late apoptotic EPCs as compared with the control group (0.054 ± 0.03% vs. 0.079 ± 0.06%, P=0.039 and 0% (0-3.4%) vs. 5% (0-14%), P=0.03, respectively). In patients with AR, circulating EPCs correlated negatively with septal thickness (r=-0.47, P=0.01), whereas late apoptotic EPCs had a negative correlation with left ventricular end-systolic diameter (r=-0.57, P=0.01). CONCLUSIONS: Patients with AR have fewer EPCs and late apoptotic EPCs. These data suggest an impaired valvular endothelial cell regenerative process in patients with AR.

Thoracic aortic atherosclerosis in patients with aortic regurgitation.

OBJECTIVE: Hemodynamic forces are potential determinants of aortic atherosclerosis. Aortic regurgitation (AR) alters the flow pattern in the aorta. However, the association between AR and aortic atherosclerosis is not well known. METHODS: We assessed the presence, extent and distribution of atherosclerotic lesions in the aorta of 42 patients with chronic AR and compared them to 40 patients with similar risk factor profile for atherosclerosis and no valvular disease. RESULTS: There was no difference in the extent of atheroma in the ascending aorta and aortic arch between patients with and without AR. Descending aortic atheroma was evident in 25 patients with AR (60%) and 12 patients without AR (30%, p=0.01). AR was found to be the only predicting factor for the presence of aortic atherosclerosis in the descending aorta (odds ratio 4.1; 95% CI 1.2-14.3, p=0.03). CONCLUSIONS: There is an increased prevalence of descending aortic atherosclerosis in patients with significant AR.

Differential effects of coronary artery stenosis on myocardial function: the value of myocardial strain analysis for the detection of coronary artery disease.

BACKGROUND: Speckle-tracking imaging is a novel method for assessing left ventricular (LV) function and ischemic changes. The aim of this study was to assess the predictive value of two-dimensional longitudinal strain in the detection of longitudinal LV dysfunction and the identification of coronary artery disease (CAD) in patients hospitalized with angina. METHODS: Two-dimensional strain software was extended to allow the analysis of numerous longitudinal strain traces in the entire left ventricle and generate a histogram of peak systolic strain (PSS) values for the left ventricle and for each coronary territory. In each histogram, the value of the 10% worst strain values (PSS(10%)) was determined. Global strain, segmental PSS, and PSS(10%) were analyzed in 97 patients hospitalized with angina and had normal LV function, who underwent coronary angiography, and 51 patients with low probability of CAD. Echocardiography was performed 2.9 ± 2 days after admission. RESULTS: Sixty-nine patients had significant CAD on coronary angiography. Significant differences were observed in all strain parameters between patients with and without CAD. PSS(10%) showed the best accuracy in detecting CAD, with an area under the receiver operating characteristic curve of 0.85. The areas under the curve for global strain and segmental PSS were 0.80 and 0.76, respectively. The optimal cutoff for PSS(10%) was -13.9%, with sensitivity and specificity of 86% and 75%, respectively. PSS(10%) was better than segmental PSS in the detection of CAD in each coronary territory. CONCLUSIONS: In patients hospitalized with angina who have significant CAD on coronary angiography, longitudinal systolic function is impaired. Histogram analysis improved the accuracy of longitudinal strain analysis in detecting global and regional impaired function.

Accuracy and long-term prognostic value of pacing stress echocardiography compared with dipyridamole tl201 emission computed tomography in patients with a permanent pacemaker and known or suspected coronary artery disease.

OBJECTIVES: Myocardial ischemia is difficult to assess by noninvasive methods in patients with a permanent pacemaker. Pacing stress echocardiography (PASE) has been used successfully in the detection of coronary artery disease (CAD). However, there are no data comparing PASE and other methods. METHODS: We compared agreement and accuracy of PASE and radionuclide tomography (SPECT) in detecting CAD in 58 patients, mean age 75 +/- 7 years, with a permanent pacemaker and known or suspected CAD. Thirty-nine patients underwent coronary angiography. The prognostic value of these tests was determined by prediction of cardiac events and cardiac death. RESULTS: PASE and SPECT were positive in 39 and 43 patients, respectively. The agreement between the tests was 75%; kappa value 0.64. The sensitivity was 87 and 96% and the specificity 78 and 57%, respectively. With median follow-up of 51 months, there were 24 cardiac events and 8 cardiac deaths. Multivariable analysis determined that positive PASE was the only independent predictive factor associated with cardiac events and cardiac death. CONCLUSIONS: PASE is a feasible and effective method for detection of significant CAD in patients with permanent-pacemaker and allows effective risk stratification. PASE merits further study in larger prospective comparative studies.