Discussion
We evaluated the prevalence of PH and prognostic significance of right heart parameters in patients with CA. Four key points can be inferred from our analysis: (1) PH is highly prevalent at the time of CA diagnosis, (2) while isolated precapillary PH is rare, IPCPH and CPCPH occur frequently in CA, (3) right ventricular dysfunction correlates better with amyloid burden than with haemodynamic markers of pulmonary vascular disease and (4) TPG, right and left ventricular ejection fractions are associated with adverse outcomes in CA. The key findings of this manuscript are summarized in figure 5.
Figure 5Summary of key findings from our analysis. (A) PH is highly prevalent in cardiac amyloidosis (CA); while isolated post-capillary PH (IPC-PH) is most common, a substantial proportion of patients have combined post and pre-capillary PH (CPCPH). (B) Right ventricular dysfunction, as defined using RV ejection fraction and strain, correlates with amyloid burden as assessed by extracellular volume (ECV). (C) In Random Forest modelling, TPG, LVEF and RVEF were the most important variables in predicting major adverse cardiovascular events (MACE). DPG, diastolic pulmonary gradient; ECV, extracellular vol; EF, ejection fraction; LV, left ventricle; PA, pulmonary artery; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RV, right ventricle; TPG, transpulmonary gradient.
Prevalence and hemodynamic profiles of PH in CA
Our study highlights the prevalence and haemodynamic profile of PH in patients with CA. PH was nearly ubiquitous in our cohort with over 88% of patients having mean pulmonary artery pressure ≥25 mm Hg. Additionally, PH was present at the time of diagnosis in 91% of cases, highlighting the need for earlier diagnosis of CA prior to onset of IPCPH and CPCPH. While we did not use a non-CA control group, these rates appear to be much higher than previous reported rates in the general HFpEF and HFrEF populations.8 19 Isolated precapillary PH was rare in our cohort, supporting the theory that pulmonary vascular disease rarely occurs in the absence of increased left-sided filling pressures. Yet, over one-fourth of patients had haemodynamic profiles consistent with CPCPH, suggesting that some element of intrinsic pulmonary vascular disease is not uncommon in CA. Pulmonary vascular disease is typically a late complication of left heart failure and is thought to occur due to the long-term effects of vascular distension and inflammation on the pulmonary vasculature.20 21
The treatment of PH in the setting of left heart disease is complicated as excessive pulmonary vasodilation can worsen left-heart failure. However, despite these reasonable concerns, several recent pharmaceutical and interventional trials targeting the pulmonary vasculature have shown benefit in CPCPH.22–25 Whether targeted PH therapies may similarly benefit appropriately phenotyped patients with CA with CPCPH is currently unknown.
Correlation of RV function with pulmonary vascular haemodynamics and amyloid burden
Interestingly, contrary to our initial hypothesis, right ventricular function—as assessed using CMR—did not significantly differ between PH groups. Instead, right ventricular function correlated much more closely with amyloid burden as assessed by ECV than with haemodynamic PH profile. ECV has been previously shown to correlate with histologic amyloid burden.26 27
One potential explanation is that right ventricular dysfunction in CA may be driven by intrinsic right ventricular myopathy from amyloid deposition rather than from PH. Unlike other aetiologies of left heart failure, CA is an infiltrative cardiomyopathy, which frequently involves both ventricles. In previous biopsy and autopsy studies, amyloid deposits were identified in the RV in 85%–95% of patients with CA.28 29 Additionally, apical sparing of longitudinal strain—a classical finding in the LV—also occurs in the RV in CA. Both of these findings support the theory that amyloid infiltration of the RV directly contributes to right ventricular dysfunction in this population.
Pulmonary vascular disease, right heart failure, and outcomes
Given the small size of our cohort and limited number of patients with precapillary PH and without PH, our study was underperformed to detect differences in clinical outcomes across PH haemodynamic profiles. Additionally, the overall poor prognosis of the cohort further complicated our ability to detect intergroup differences in outcomes. Further studies—ideally in larger multicentre cohorts—are needed to determine whether PH haemodynamic profiles are prognostic in patients with CA.
We did find that TPG was associated with MACE in CA. Elevation in TPG is indicative of intrinsic pulmonary vascular disease and can differentiate CPCPH from PHLHD.12 Increased TPG has been previously associated with increased mortality in the HFpEF and HFrEF populations.11 Additionally, we validate previous studies in demonstrating an association between left and right ventricular function and adverse events in CA.30–33 Given the small size of our cohort, we were unable to robustly control for covariates. Therefore, the relationships between these parameters and outcomes should be viewed as exploratory.
Limitations
Due to the small size of our cohort and the retrospective nature of the study, there exists the possibility of type II error due to confounding. With the size of our cohort, we additionally could not perform multivariable analysis to control for confounders due to model overfitting.34 35 Therefore, our findings should ideally be validated in larger multicentre cohorts, which would enable more robust controlling for covariates. Given its retrospective nature, RHC and CMR were not performed simultaneously. It is, therefore, possible that these studies may have been performed under different cardiac loading conditions. However, in the vast majority of patients, CMR and RHC were performed within 40 days of each other. Additionally, RHC and CMR were performed for clinical indications, which may select for sicker patients. However, as discussed above, a majority of RHCs were performed at the time of diagnosis during endomyocardial biopsy. Even after excluding RHC done for clinical indications, the prevalence of PH was 91%, even higher than in the overall cohort. Our study also included both AL and ATTR cardiac amyloidosis, which may differ in their cardiac manifestations. While we were unable to further subdivide the cohort due to sample size, we did not note any significant differences in subtype prevalence among the haemodynamic profiles. Finally, based on survival data and CMR parameters, our cohort demonstrates advanced stage disease. It is unknown whether these results can be generalised to patients with CA with milder disease.