Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis

PAPER OF MARCH 2015

Authors: Nicole B. Cyrille, Jeff Goldsmith, Julissa Alvarez, Mathew S. Maurer1

American journal of cardiology. 2014;114(7):1089-1093.

Presented by: Angelos G. Rigopoulos, 1st Department of Internal Medicine, Leopoldina Hospital, Schweinfurt, Germany.

Background:

The prevalence of specific electrocardiographic abnormalities in cardiac amyloidosis is important to know in order to be able to define the diagnostic competence of the electrocardiogram (ECG). Classical knowledge about cardiac amyloidosis emphasizes the appearance of ‘low voltage’ in electrocardiogram as a clinical marker of the disease, especially in patients with echocardiographically detectable cardiac hypertrophy. Nevertheless, the sensitivity of low voltage in cardiac amyloidosis remains largely unknown. Most data on ECG features derive from studies on light chain (AL) amyloidosis whereas little is known about ECG abnormalities in transthyretin (ATTR) amyloidosis. In general, the prevalence of low voltage varies greatly from 46-70%, depending obviously on the different cardiac involvement in various studies as well as on the criteria used for the measurement of voltage in ECG. A recent study by Mussinelli R, et al2 has shown that the use of Sokolow-Lyon Index < 1.5mV  has the highest sensitivity and specificity in identifying cardiac AL patients, in comparison to other ECG voltage scores.

Aim of the study:

The study aimed at determining the prevalence of various ECG features in a combined cohort of patients with AL, mutant ATTR (ATTRmt) and wild type ATTR (ATTRwt) and their prognostic significance. The hypothesis was that if low voltage be an early marker of cardiac amyloidosis, it would be present in most patients with various amyloid types and (as an early marker of the disease) would bear no prognostic significance.

Summary:

In this study 200 consecutive patients with cardiac amyloidosis were enrolled: 110 with AL, 45 ATTRmt and 45 ATTRwt. Inclusion criteria were biopsy proven cardiac amyloidosis or Congo red staining in another organ and echocardiography compatible with cardiac amyloidosis or TTR mutation and echocardiography compatible with amyloidosis. Patients had a 12-lead ECG and were followed for a mean time of 616 days (6-4660) for cardiac events.

Low voltage of the QRS amplitude was defined according to the criteria depicted in Table 1.
Table 1: Criteria for ECG voltage measurement

Left ventricular hypertrophy was defined according to the criteria of Sokolow-Lyon as well as the Cornell criteria.
Table 2: ECG Criteria for left ventricular hypertrophy

Other ECG features such as pseudoirfarction pattern, delayed R-progression in the precordial leads, and QT delay was also measured, while echocardiographic parameters pertaining to left ventricular hypertrophy (LV mass) were also noted.

The tree groups of patients differed substantially in age, with ATTRwt having the highest mean age, gender, with most patients being male but in different proportions (ATTRwt 91%, ATTRmt 78% and AL 67%) and race with white patients being the majority in ATTRwt (80%) and AL (53%) and the minority in ATTRmt (31%). Moreover, a significant majority of patients with AL (61%) were highly symptomatic (NYHA III-IV) on presentation (49% of ATTRmt and 36% of ATTRwt).

It should be emphasized that most patients with ATTRmt had one of two mutations (Val 122Ile 62% and Thr60Ala 16%) which are known to produce exclusively or predominantly a cardiac phenotype.

The prevalence of low voltage based on limb leads, low voltage in precordial leads or pseudoinfarction pattern was low in this study and did not differ among the three groups. Low voltage based on Sokolow-Lyon criteria (60%) and poor R-wave progression (64%) was more frequent and also did not differ among groups.

During follow-up 125 patients had events (72 were hospitalized, 78 died and 25 received heart transplantation). Univariate analysis indicated AL amyloid, low voltage in limb leads, Sokolow index ≤1,5 mV an abnormal voltage to mass ratio as predictors of adverse outcome, whereas only Sokolow index ≤1,5 mV was independently associated with outcome on multivariate analysis. AL amyloid was associated with 88% higher mortality and 72% higher event rate in comparison to ATTR amyloidosis.

The prevalence of electrocardiographic voltage characteristics (pseudoinfarct pattern, poor R wave progression, low voltage in limb or precordial leads, Sokolow index ≤ 1.5mV, total QRS amplitude, left ventricular hypertrophy) were not significantly different in the different types of amyloid. Atrial fibrillation in contrast to sinus rhythm as well as 1st degree atrioventricular block was more common in ATTRwt, however, aetiology could be related to the older age of this group.

Conclusion:

The prevalence of low voltage in cardiac amyloidosis is dependent on the definition and method used for its measurement, with Sokolow index ≤ 1.5mV showing the highest prevalence and association with adverse outcomes. This study suggests that low voltage is a relatively late finding in cardiac amyloidosis and may not be useful for early identification.

Comments:

This study provides further input in regarding low voltage in ECG as a marker of cardiac amyloidosis. It does not contradict the classical paradigm, but rather outlines temporal association of this finding as a marker of the disease as well as its prognostic significance: low voltage (depending on its definition) is probably not an early feature of cardiac amyloidosis but rather a marker of advanced disease. Presence of low voltage as expressed by the Sokolow-Lyon index (≤ 1.5 mV), which is, however, rarely used for measurement of low voltage in the clinical setting, indicates increased sensitivity and bears prognostic significance. The obvious limitations of this study (retrospective study from one centre, only descriptive data) as well as the possible referral bias (most patients have advanced disease) do not lessen the importance of the findings.