Ventilatory efficiency in cardiac amyloidosis-A systematic review and meta-analysis

Abstract

In cardiac amyloidosis (CA) cardiopulmonary exercise testing (CPET) is underexplored. This study evaluated exercise limitations in CA using CPET, focusing on the ventilation-to-carbon dioxide production (VE/VCO₂) slope and peak oxygen uptake (VO₂). Seventeen studies involving 1505 patients were analyzed and systematically reviewed according to PRISMA reporting guidelines. Subgroup analyses assessed differences by diagnosis (ATTR vs. AL), CPET modality, and age. The cohort included 12% with AL, 80% with ATTR (23% hereditary [ATTRv], 70% wild-type [ATTRwt], 7% unspecified), and 8% unidentified subtypes. VE/VCO₂ slope was elevated across ATTR subgroups: 38.4 (95% CI: 36.9-40.0, I² = 57%) in ATTRwt and 37.9 (95% CI: 35.1-40.7, I² = 70%) in ATTRv. ATTR patients were older than AL patients by 9.0 years (95% CI: 0.4-17.6, I² = 88%) and had a higher VE/VCO₂ slope: 2.5 (95% CI: 0.2-4.8, I² = 0%). CPET modality influenced peak VO₂, which was lowest for treadmill exercise (13.7, 95% CI: 12.7-14.8, I² = 0%, mL/min/kg) compared to upright cycle ergometry (14.7, 95% CI: 14.3-15.1, I² = 33%) and semi-recumbent cycle ergometry (14.5, 95% CI: 14.1-14.9, I² = 28%). A high VE/VCO₂ slope characterizes both ATTRwt and ATTRv, while AL patients are younger with lower VE/VCO₂ slope levels. Peak VO₂ in ATTR patients may depend on exercise modality.

Keywords: amyloidosis; cardiomyopathy; exercise testing; heart failure; risk prediction.

FIGURE 1

Flowchart of the study selection process. The flowchart in Figure 1 illustrates the study selection process for identifying studies relevant to cardiopulmonary exercise testing (CPET) in cardiac amyloidosis. Out of 85 initially identified records, 37 were excluded based on title screening, and 20 were excluded as off‐topic after screening articles. From 28 articles identified based on titles and abstracts, full texts were screened, resulting in the exclusion of five studies due to potential cohort overlap and six studies for missing key CPET variables. Ultimately, 17 studies were included in the final analysis. Of the 17 included studies three studies had to be excluded after subgroup analysis due to submaximal exercise and short exercise duration (8 minutes). N, number of studies.

FIGURE 2

Comparative analysis of ATTR versus AL patients. Figure 2 contains two forest plots comparing patients with ATTR and AL. (a) Compares mean age, showing that ATTR patients are significantly older by 9.0 years (95% CI: 0.4–17.6, p = 0.04), with high variability between studies (I ² = 87.9%). (b) Compares VE/VCO₂ slope, indicating slightly reduced ventilatory efficiency in AL patients, with a mean difference of 2.5 (95% CI: 0.2–4.8, p = 0.03) and low variability (I ² = 0%). Each study is represented by a square (mean difference) and horizontal line (confidence interval), while the diamond at the bottom shows the pooled overall estimate. AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; Chi², chi‐squared statistic; CI, confidence interval; df, degrees of freedom; I ², heterogeneity index; MD, mean difference; SD, standard deviation; Tau², between‐study variance; VE/VCO₂, ventilation to carbon dioxide production ratio.

FIGURE 3

Effect of exercise modality on peak VO₂. Figure 3 shows a forest plot, that summarizes the effect of exercise modality on peak VO₂ during CPET, comparing treadmill, upright, and semi‐recumbent cycle ergometry. Treadmill testing yielded the lowest peak VO₂. Each study's contribution is shown by a square (mean VO₂) and horizontal line (confidence interval), with pooled subgroup means represented by diamonds. CI, confidence interval; I ², heterogeneity; MRAW, mean random effects model; p, probability value; RE, random effects; VO₂, oxygen uptake; τ ², tau‐squared (between‐study variance); χ ², chi‐squared (test of heterogeneity).