Prospective Evaluation of Blood Pressure Monitoring and Baroreceptor Reflex Sensitivity (BRS) in Patients with AL Amyloidosis: Prognostic and Pathophysiologic Implications

The prognosis of patients with AL amyloidosis depends on the degree of cardiac dysfunction. Elevated cardiac troponin levels and of NTproBNP identify patients at high risk (stage 3 per Mayo stage); very high levels of NTproBNP are further associated with quite poor outcomes. Low blood pressure (BP) is associated with poor prognosis in patients with Mayo stage-3 disease (Wechalekar et al Blood 2013). BP depends on cardiac output and is tightly regulated by the autonomic nervous system (ANS), which is also commonly affected and deregulated in AL amyloidosis. However, the prognostic role of BP has not been evaluated prospectively and the measurement of BP in patients with AL has not been standardized as a prognostic factor. In addition, the importance of the deregulation of ANS in AL amyloidosis as a determinant of BP has not been evaluated. Baroreceptor reflex sensitivity (BRS) is implicated in the homeostatic regulation of the cardiovascular system and can be measured as a surrogate for the ANS effect on BP. In the current study we prospectively evaluated office and 24h ambulatory BP and calculated cardiac BRS in newly diagnosed patients with AL amyloidosis.

All patients underwent office BP measurements, 24h ambulatory BP monitoring and a simultaneously electrocardiographic and non-invasive BP monitoring (Finometer), under standardized conditions for 15min. Standard office BP consisted of three BP measurements taken at a 1-min intervals, at sitting position, averaged to obtain a single systolic and diastolic office BP value. Ambulatory BP monitoring was performed on a usual working day. BP recordings were obtained automatically at 15-min intervals throughout the 24h period. Daytime was defined as the interval between 09:00h and 21:00h and nighttime was the interval between 01:00h and 06:00h. BRS was expressed as the alpha-index (a-index), which was estimated by means of power spectral analysis.

This prospective analysis included 50 consecutive patients with biopsy confirmed AL amyloidosis. Median age was 65 (range 40-84) and 50% were males. Heart was involved in 64%, kidneys in 70% and nervous system in 20%. Per Mayo stage, 10% were stage-1, 60%-2 and 30%-3 and 12% had NTproBNP≥8500 ng/L. Median eGFR was 63 ml/min/1.73 m2 (by MDRD formula). Primary treatment was bortezomib-based (VD, VCD or BMDex) in 80% and 20% received MDex.

Median office systolic BP (SBP) was 118 mmHg and median diastolic BP (DBP) was 72 mmHg. SBP was lower in stage 2 vs stage 1 and stage 3 vs either stage 2 or stage 1 patients (p=0.026); there was no significant difference in the DBP between groups. The median level of the mean 24h ambulatory SBP was 112.5 mmHg and for DBP was 69.5 mmHg; again, advanced Mayo stage was associated with lower mean 24h SBP (p=0.048). While 20% of patients had office SBP<100 mmHg and 24% had 24h SBP<100 mmHg, none of those with Mayo stage 1, 13% of patients with Mayo stage-2 and 33% of those with stage-3 had office SBP<100 mmHg. For 24h mean SBP, none with stage 1, 23% with stage 2 and 42% with stage 3 had SBP<100 mmHg. Lower levels of SBP were associated with inferior survival and this was more pronounced in patients with Mayo stage 2 or 3 disease. More specifically either office SBP<100 mmHg (6 months vs not reached) (p<0.001) or mean 24h SBP<90 mmHg (2 months vs not reached) (p<0.001) were associated with poor survival and early death. Analysis of 24h ambulatory BP monitoring provided data of higher BP fluctuations among patients with less severe or no heart involvement, while more often patients with Mayo stage 3 had higher nighttime vs daytime SBP values than stage 2 or stage 1 patients.

Median a-index was 2.85 (range 0.4-5.85) and was lower in patients with advanced cardiac involvement. Importantly, a-index was lower in patients who had nerve involvement (median 1.6 vs 3.3, p=0.016). Thus, a-index reflected both cardiac and nerve involvement by AL amyloidosis. Low a-index was associated with early death: 25% of those with a-index<2.14 died within 3 months from initiation of therapy but there were no early deaths among patients with a-index ≥2.14.

In conclusion, low BP, either measured in a sitting position as in standard office visits or by means of 24h ambulatory measurement, is associated with poor prognosis in patients with AL amyloidosis. Impaired BRS is associated with advanced cardiac and nerve involvement and risk of early death. Further analysis of the data obtained during 24h ambulatory BP monitoring and BRS is ongoing.