Hemodynamic, Functional and Structural Markers of Vascular Involvement in Primary Systemic Light Chain (AL) Amyloidosis

Abstract Light chain (AL) amyloidosis is characterized by the extracellular deposition of clonal light chain-derived amyloid fibrils in various tissues. Kidneys and heart are most commonly affected; clinically non detectable deposits in other tissues may also result in significant dysfunction. Amyloid deposits within the wall of the arteries or direct toxicity of light chains may cause arterial dysfunction in patients with AL amyloidosis, with cardiovascular consequences. Endothelial dysfunction, subclinical atherosclerosis of the carotid arteries and stiffening of the arterial tree are commonly found as deleterious vascular phenotypes and are considered surrogate markers of cardiovascular disease and outcome. Matrix metalloproteases, advanced glycation products, endothelial dysfunction and neuroendocrine signaling are implicated in arterial dysfunction and are affected in AL amyloidosis. However, arterial involvement in AL has not been evaluated thoroughly. In order to evaluate vascular dysfunction in patients with AL amyloidosis we evaluated non-invasively acquired markers which may be indicative of vascular involvement: hemodynamic [reflected waves and aortic blood pressures (BP)], functional [flow-mediated dilatation and carotid-femoral pulse wave velocity (PWV)] and structural [intima-media thickness (IMT) and the presence of plaques in the carotid arteries] markers of vascular damage were measured. Ninety-one (91) consecutive newly diagnosed patients with systemic AL were prospectively studied and compared to 91 controls matched 1:1 for traditional risk factors of cardiovascular disease (age, gender, smoking, hypertension, hyperlipidemia, diabetes) and for the presence of coronary artery disease. The median age of patients with AL was 65 years (range 40-83), 56% were males, 77% had renal and 57% cardiac involvement. Median NTproBNP was 1420 pg/ml, 25%, 49% & 26% were Mayo stage 1, 2 & 3 respectively, median eGFR was 66 ml/min/1.73 m2and median involved FLC (iFLC) level was 189 mg/L. First we compared indices of vascular damage between AL patients and matched controls: arterial stiffness (PWV: 10.4±3.0 vs 8.6±3.7 m/sec, p=0.002) and arterial wall thickness in the internal carotid artery (IMT: 0.76±0.21 vs 0.68±0.21 mm, p=0.017) were significantly higher in AL patients. Thus, subclinical vascular damage, independent from traditional factors of vascular dysfunction, is present in patients with AL. Peripheral systolic and diastolic blood pressure and aortic systolic, diastolic and pulse pressure (p≤0.001) and reflected waves (augmentation index (AI), p=0.045) were significantly lower in AL patients than in controls. After adjustment for NTproBNP levels, as a marker of cardiac dysfunction, the differences in blood pressures (systolic, diastolic and pulse pressure) remained significant (p≤0.008 for all). Thus, despite increased arterial stiffness, dysfunctional vasculature results in paradoxically lower systolic and diastolic blood pressure, a hallmark of AL amyloidosis, independently from the degree of cardiac dysfunction. We then examined possible associations of markers of AL with the indices of vascular dysfunction, after adjustment for risk factors of cardiovascular disease. The level of iFLCs was an independent determinant of lower peripheral systolic (p=0.021) and aortic systolic (p=0.009) and pulse pressure (p=0.013), hsTnT (p=0.016) and NTproBNP (p=0.001) levels were independent determinants of arterial stiffness (PWV). In a multivariate model mean blood pressure and NTproBNP were the only determinants of PWV. NTproBNP also correlated with the presence of plaques in the internal carotid arteries (p=0.006) independently of other risk factors of vascular disease. Thus, markers of cardiac dysfunction and the load of FLCs were associated with vascular dysfunction. Our results suggest vascular involvement in patients with AL amyloidosis, reflected at low aortic blood pressures, increased arterial stiffness and wall thickness in the internal carotid arteries. The association of the amount of light chains with aortic blood pressure suggests a role of the toxic light chain. The observed association of arterial stiffness with markers of heart involvement is indicative of a parallel process of heart and vascular injury in AL amyloidosis. Further research, to assess the clinical utility of markers of vascular damage in AL amyloidosis is needed. Disclosures No relevant conflicts of interest to declare.