Low QRS Voltages in Cardiac Amyloidosis: Clinical Correlates and Prognostic Value

Abstract

Background: Low QRS voltages (LQRSVs) are a common electrocardiographic feature in patients with light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) cardiac amyloidosis (CA).

Objectives: The aim of this study was to identify clinical and echocardiographic correlates of LQRSV and to investigate their prognostic significance in patients with CA.

Methods: This was a multicenter, retrospective study performed in 6 CA referral centers including consecutive patients with AL and ATTR CA. LQRSVs were defined as a QRS amplitude ≤5 mm (0.5 mV) in all peripheral leads. The study outcome was cardiovascular (CV) mortality.

Results: Overall, 411 (AL CA: n = 120, ATTR CA: n = 291) patients were included. LQRSVs were present in 66 (55%) patients with AL CA and 103 (35%) with ATTR CA (P < 0.001). In AL CA, LQRSVs were independently associated with younger age (P = 0.015), higher New York Heart Association functional class (P = 0.016), and natriuretic peptides (P = 0.041); in ATTR CA, LQRSVs were independently associated with pericardial effusion (P = 0.008) and lower tricuspid annulus peak systolic excursion (P = 0.038). During a median follow-up of 33 months (Q1-Q3: 21-46), LQRSVs independently predicted CV death in both AL CA (HR: 1.76; 95% CI: 2.41-10.18; P = 0.031) and ATTR CA (HR: 2.64; 95% CI: 1.82-20.17; P = 0.005). Together with the National Amyloidosis Centre (NAC) staging, LQRSVs provided incremental prognostic value in ATTR CA (AUC for NAC model: 0.83 [95% CI: 0.77-0.89]; AUC for NAC + LQRSV model: 0.87 [95% CI: 0.81-0.93]; P = 0.040).

Conclusions: LQRSVs are common but not ubiquitous in CA; they are more frequent in AL CA than in ATTR CA. LQRSVs reflect an advanced disease stage and independently predict CV death. In ATTR CA, LQRSVs can provide incremental prognostic accuracy over the NAC staging system in patients with intermediate risk.

Keywords: AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; ATTR-v, variant transthyretin; ATTR-wt, wild-type transthyretin; AUC, area under the curve; BNP, B-type natriuretic peptide; CA, cardiac amyloidosis; CMR, cardiac magnetic resonance; CV, cardiovascular; ECG, electrocardiogram; LQRSV, low QRS voltages; LV, left ventricle; LVEDD, left ventricular end-diastolic diameter; NAC, National Amyloidosis Centre; NT-proBNP, N-terminal pro–B-type natriuretic peptide; NYHA, New York Heart Association; ROC, receiver-operating characteristic; RV, right ventricular; TAPSE, tricuspid annulus peak systolic excursion; cardiac amyloidosis; echocardiography; electrocardiography; low QRS voltages; prognostic significance; risk stratification.

Graphical abstract

Figure 1

Survival Curves Stratified by the Presence or Absence of LQRSV Survival curves based on Kaplan-Meier survival analysis in patients with (A) light chain cardiac amyloidosis (AL CA) and (B) transthyretin cardiac amyloidosis (ATTR CA) stratified by the presence (red line) or absence (blue line) of low QRS voltages (LQRSV) at baseline 12-lead electrocardiography. Patients with LQRSV, both with AL CA and ATTR CA, manifested a shorter survival compared with those without LQRSV.

Figure 2

Survival in ATTR CA Based on NAC Staging System and LQRSV Survival curves performed with Kaplan-Meier analysis for patients with ATTR CA based on (A) National Amyloidosis Center (NAC) staging system alone and (B) including LQRSV. By adding LQRSV to the NAC staging system, significant differences in survival probability were found among NAC stage II versus NAC stage II + LQRSV (P = 0.032) but not for NAC stage I versus NAC stage I + LQRSV and NAC stage III versus NAC stage III + LQRSV. Abbreviations as in Figure 1.

Figure 3

Time-Dependent ROC Analysis The area under the curve (AUC) improves significantly after the first 6 months (adjusted Blanche’s P value <0.001) when LQRSV information is added to NAC stratification. Net reclassification improvement = 0.24 (95% CI: −0.098 to 0.338). ∗P < 0.05 between AUCs up to 36 months of follow-up. ROC = receiver-operating characteristic; other abbreviations as in Figures 1 and 2.

Central Illustration

Prevalence, Predictors, and Prognostic Significance of Low QRS Voltages in Cardiac Amyloidosis Low QRS voltages (LQRSV) are more frequent in light chain cardiac amyloidosis (AL CA) than in transthyretin cardiac amyloidosis (ATTR CA) and are more commonly identified in younger patients with AL CA with a higher New York Heart Association functional class, natriuretic peptides, advanced left ventricular (LV) remodeling and systolic right ventricular (RV) and LV dysfunction or in patients with ATTR CA with atrial fibrillation, pericardial effusion, lower LV mass, and systolic RV dysfunction. Moreover, LQRSVs are a significant risk factor for cardiovascular mortality in both AL- and ATTR CA. NYHA = New York Heart Association; RV = right ventricular; AL = light chain amyloidosis; ATTR = transthyretin amyloidosis; LQRSV = low QRS voltages.

Figure 4

Electrocardiographic and Histologic Features of a Patient With ATTR CA Electrocardiographic and histologic features of a 74-year-old patient with ATTR CA who died from refractory heart failure. (A) Basal 12-lead electrocardiogram showing LQRSV. (B) An autopsy specimen of the myocardium showing diffuse and massive amyloid interstitial deposition (black arrow) together with rarefied and atrophic cardiomyocytes (black asterisk) (sulfated Alcian blue stain, scale bar = 200 μm). Abbreviations as in Figure 1.