Combined Cardiac Damage Staging with Echocardiography and Catheterization: the Best of Both Worlds?

Calcific aortic stenosis (AS) is the most frequent clinically relevant valvular heart disease in developed countries, with a prevalence that is projected to increase in the future owing to population aging.1Nkomo V.T. Gardin J.M. Skelton T.N. et al.Burden of valvular heart diseases: a population-based study.Lancet. 2006; 368: 1005-1011Abstract Full Text Full Text PDF PubMed Scopus (3626) Google Scholar In the absence of any effective pharmaceutical treatment, aortic valve replacement (AVR), either surgical or transcatheter, is currently the only treatment option.2Otto C.M. Nishimura R.A. Bonow R.O. et al.2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2021; 143: e72-e227PubMed Google Scholar Symptom onset (ie, shortness of breath, chest pain, or syncope on exertion) is a pivotal point in the disease's natural history and is associated with worse outcomes. Nevertheless, symptom evaluation in elderly, sedentary, comorbid patients is often challenging with dyspnoea and fatigue frequently self-attributed to old age. Besides symptoms, indications for AVR include several valve-specific hemodynamic parameters (valve area, transvalvular mean gradient, and maximal transvalvular velocity); the only nonvalvular parameter considered by current guidelines is the left ventricular ejection fraction (LVEF). A cutoff value of < 50% is a class I indication for AVR in asymptomatic patients with severe aortic stenosis in both American and European guidelines, with a higher cutoff value of < 55% also being considered in European guidelines as a class IIa indication.2Otto C.M. Nishimura R.A. Bonow R.O. et al.2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2021; 143: e72-e227PubMed Google Scholar,3Vahanian A. Beyersdorf F. Praz F. et al.ESC/EACTS Scientific Document Group. 2021 ESC/EACTS guidelines for the management of valvular heart disease.Eur J Cardiothorac Surg. 2021; 60: 727-800Crossref PubMed Scopus (425) Google Scholar Nevertheless, calculating LVEF can be challenging owing to poor image quality, left ventricular (LV) hypertrabeculation, or arrhythmia. Furthermore, LVEF gives only a crude estimation of LV systolic function and does not always reflect the true capacity of the cardiac muscle to generate stroke volume. For example, patients with marked LV hypertrophy, small LV cavity size, or reduced longitudinal function, as in cardiac amyloidosis or small vessel disease, typically exhibit low stroke volumes despite normal or near-normal LVEF. For this reason, researchers sought to find additional markers to quantify the effects of chronic pressure overload on the LV and improve risk stratification. These markers were initially focused on LV fibrosis, included global longitudinal strain according to transthoracic echocardiography (TTE), late gadolinium enhancement, and T1 mapping with the use of cardiac magnetic resonance imaging, and cardiac biomarkers, and were found to have an incremental value for predicting mortality in AS.4Meredith T. Roy D. Hayward C. et al.Strain assessment in aortic stenosis: pathophysiology and clinical utility.J Am Soc Echocardiogr. 2023; PubMed Google Scholar Nevertheless, the heart's maladaptive response to chronic pressure overload is not limited to the LV but extends upstream, into the left atrium (LA), pulmonary vasculature, and ultimately into the right chambers. Consequently, Généreux et al. took a step further and introduced the concept of cardiac damage staging in 2017.5Genereux P. Pibarot P. Redfors B. et al.Staging classification of aortic stenosis based on the extent of cardiac damage.Eur Heart J. 2017; 38: 3351-3358Crossref PubMed Scopus (368) Google Scholar They studied TTE data from the Placement of Aortic Transcatheter Valves (PARTNER) 2 trials, which included intermediate-risk patients with symptomatic severe AS who underwent AVR by surgical or transcatheter approach. The patients were classified into 5 stages: stage 0, no cardiac damage; stage 1, LV damage; stage 2, LA or mitral valve damage; stage 3, pulmonary artery vasculature/tricuspid valve damage; and stage 4, right ventricle damage (Table 1). Cardiac damage staging was associated with a prognostic value for 1-year survival. Later, the concept of cardiac damage was validated in patients with moderate aortic stenosis and patients without cardiac symptoms, demonstrating an incremental prognostic value for each stage of damage extension.Table 1Comparison of cardiac damage staging criteria used in key studies for risk stratification of patients with aortic stenosisGénéreux et al.5Genereux P. Pibarot P. Redfors B. et al.Staging classification of aortic stenosis based on the extent of cardiac damage.Eur Heart J. 2017; 38: 3351-3358Crossref PubMed Scopus (368) Google Scholar (2017)Tastet et al.10Tastet L. Tribouilloy C. Maréchaux S. et al.Staging cardiac damage in patients with asymptomatic aortic valve stenosis.J Am Coll Cardiol. 2019; 74: 550-563Crossref PubMed Scopus (149) Google Scholar (2019)Maeder et al.6Maeder M.T. Weber L. Weilenmann D. et al.Invasive hemodynamic staging classification of cardiac damage in patients with aortic stenosis undergoing valve replacement.Can J Cardiol. 2020; 36: 1667-1674Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar (2020)Vollema et al.11Vollema E.M. Amanullah M.R. Prihadi E.A. et al.Incremental value of left ventricular global longitudinal strain in a newly proposed staging classification based on cardiac damage in patients with severe aortic stenosis.Eur Heart J Cardiovasc Imaging. 2020; 21: 1248-1258Crossref PubMed Scopus (33) Google Scholar (2020)Okuno et al.8Okuno T. Heg D. Lanz J. et al.Refined staging classification of cardiac damage associated with aortic stenosis and outcomes after transcatheter aortic valve implantation.Eur Heart J Qual Care Clin Outcomes. 2021; 7: 532-541Crossref PubMed Scopus (22) Google Scholar (2021)Gutierrez-Ortiz et al.12Gutierrez-Ortiz E. Olmos C. Carrión-Sanchez I. et al.Redefining cardiac damage staging in aortic stenosis: the value of GLS and RVAc.Eur Heart J Cardiovasc Imaging. 2023; 24: 1608-1617Crossref PubMed Scopus (3) Google Scholar (2023)Viva et al.7Viva T. Postolache A. Nguyen Trung M.L. et al.A new integrative approach combining right heart catheterization and echocardiography to stage aortic stenosis-related cardiac damage.Front Cardiovasc Med. 2023; 101184308Crossref PubMed Scopus (3) Google Scholar (2023)Belmonte et al.9Belmonte M. Paolisso P. Bertolone D.T. et al.Combined cardiac damage staging by echocardiography and cardiac catheterization in patients with clinically significant aortic stenosis.Can J Cardiol. 2024; 40: 643-654Abstract Full Text Full Text PDF Scopus (2) Google Scholar (2023)SymptomsSymptomaticAsymptomaticSymptomatic and asymptomaticSymptomaticSymptomaticSymptomaticSymptomaticSymptomatic and asymptomaticAS gradingSevereModerate or severeSevereSevereSevereSevereSevereModerate or severeData sourceTTETTEHC (TTE subgroup)TTETTE + HCTTETTE + HCTTE + HCCD stage0: No CDLV GLS < −18%1: LV damageLV mass index:♂ > 115 g/m2♀ > 95 g/m2E/e′ > 14LVEF < 50%LVDD ≥ grade IILV GLS ≥ −15%LVEF < 60%LVEDP > 15 mm HgLV GLS −15.8 to −18%LVDD ≥ grade IILVEF < 60%LV-GLS ≥ −17% onlyLVDD ≥ grade IILVEF < 60%LVEDP > 15mm HgLVEF < 50% in ssASLVEF < 60% in m/asAS2: LA/mitral damageLAVi > 34 mL/m2≥ Moderate MRAtrial fibrillationmPAWP > 15 mm HgLV GLS −13.2 to −15.8%Significant MR onlymPAWP > 15 mm Hg3: Pulmonary vascular/tricuspid damageSPAP ≥ 60 mm Hg≥ Moderate TRSPAP ≥ 60 mm HgPVR > 3 WoodLV GLS −10% to −13.2%3a: SPAP < 60 mm Hg;3b: SPAP ≥ 60 mm Hg; mPAP ≥ 25 mm Hg;≥ moderate TRTAPSE/SPAP < 0.35 onlymPAP ≥ 25 mm HgSPAP ≥ 60 mm Hg mPAP ≥ 25 mm HgPVR > 3 Wood4: RV/RA damage≥ Moderate RV dysfunctionS′ < 9.5 cm/sTAPSE < 17 mmSVi < 30 mL/m2mRAP > 15 mm HgLV GLS > −10%4a, 4b, 4c according to SVi < 30 mL/m2 and RV dysfunctionNo stage 4S′ < 9.5 cm/sTAPSE < 17 mmFAC < 35%SVi < 30 mL/m2CI < 1.8 L/min/m2 mRAP > 10 mm HgS′ < 9.5 cm/sTAPSE < 17 mmSVi < 30 mL/m2 mRAP > 15 mm HgThe first study by Généreux et al. serves as reference, and only new or modified criteria are described for the subsequent studies.AS, aortic valve stenosis; CD, cardiac damage; CI, cardiac index; FAC, fractional area change; HC, heart catheterization; LAVi, left atrial volume index; LV GLS, left ventricular global longitudinal strain; LVDD, left ventricular diastolic dysfunction; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; mPAWP, mean pulmonary artery wedge pressure; MR, mitral regurgitation; mRAP, mean right atrial pressure; PVR, pulmonary vascular resistance; RA, right atrium; RV, right ventricle; SPAP, systolic pulmonary artery pressure; SVi, stroke volume index; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; TTE, transthoracic echocardiography. Open table in a new tab The first study by Généreux et al. serves as reference, and only new or modified criteria are described for the subsequent studies. AS, aortic valve stenosis; CD, cardiac damage; CI, cardiac index; FAC, fractional area change; HC, heart catheterization; LAVi, left atrial volume index; LV GLS, left ventricular global longitudinal strain; LVDD, left ventricular diastolic dysfunction; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; mPAWP, mean pulmonary artery wedge pressure; MR, mitral regurgitation; mRAP, mean right atrial pressure; PVR, pulmonary vascular resistance; RA, right atrium; RV, right ventricle; SPAP, systolic pulmonary artery pressure; SVi, stroke volume index; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; TTE, transthoracic echocardiography. Maeder et al. applied the cardiac damage staging to right heart catheterization (RHC).6Maeder M.T. Weber L. Weilenmann D. et al.Invasive hemodynamic staging classification of cardiac damage in patients with aortic stenosis undergoing valve replacement.Can J Cardiol. 2020; 36: 1667-1674Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Left heart catheterization was left at the discretion of the operator. They proposed a similar 5-stage grading system (Table 1) using only invasive parameters obtained before AVR (surgical or transcatheter). After 3.8 years of median follow-up, they observed an excess mortality for patients in stages 3 and 4.6Maeder M.T. Weber L. Weilenmann D. et al.Invasive hemodynamic staging classification of cardiac damage in patients with aortic stenosis undergoing valve replacement.Can J Cardiol. 2020; 36: 1667-1674Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar More recently, echocardiographic and invasive measurements were combined to create mixed cardiac damage staging systems.7Viva T. Postolache A. Nguyen Trung M.L. et al.A new integrative approach combining right heart catheterization and echocardiography to stage aortic stenosis-related cardiac damage.Front Cardiovasc Med. 2023; 101184308Crossref PubMed Scopus (3) Google Scholar,8Okuno T. Heg D. Lanz J. et al.Refined staging classification of cardiac damage associated with aortic stenosis and outcomes after transcatheter aortic valve implantation.Eur Heart J Qual Care Clin Outcomes. 2021; 7: 532-541Crossref PubMed Scopus (22) Google Scholar Both studies used invasive right-side measurements to reclassify patients between different stages and improve risk stratification. In this issue of the Canadian Journal of Cardiology, Belmonte et al. present another combined approach that integrates both echocardiographic and RHC measurements with a median time of 5 days (interquartile range 1-27 days) between exams.9Belmonte M. Paolisso P. Bertolone D.T. et al.Combined cardiac damage staging by echocardiography and cardiac catheterization in patients with clinically significant aortic stenosis.Can J Cardiol. 2024; 40: 643-654Abstract Full Text Full Text PDF Scopus (2) Google Scholar The authors studied a cohort of 432 patients, both symptomatic and asymptomatic, derived from a single-centre observational registry of a heart valve clinic in Belgium. All patients with aortic valve area < 1.5 cm2 according to TTE were eligible, but patients with more than mild aortic regurgitation or mitral stenosis as well as with valve prosthesis were excluded. Depending on their TTE results and clinical status, patients were divided into 2 groups: 1) moderate or asymptomatic AS (m/asAS), and 2) symptomatic severe AS (ssAS). RHC was performed in all patients. According to the extent of cardiac damage at TTE, the patients of each group were categorised into 5 stages: stage 0: no cardiac damage; stage 1: LV damage (LV mass index > 95 g/m2 for women, > 115 g/m2 for men, E/e′ > 14, LVEF < 50% for ssAS and LVEF < 60% for m/asAS; stage 2: LA or mitral valve damage (LA volume index > 34 mL/m2, atrial fibrillation, ≥ moderate mitral regurgitation); stage 3: pulmonary vasculature or tricuspid valve damage (systolic pulmonary artery pressure (PAP) ≥ 60 mm Hg, ≥ moderate tricuspid regurgitation); and state 4: right ventricle damage (S′ < 9.5 cm/s, TAPSE < 17 mm, Svi < 30 mL/m2. Similar groups were used at RHC: stage 0: no cardiac damage; stage 1: LV damage (LV end-diastolic pressure > 15 mm Hg); stage 2: LA or mitral valve damage (mean pulmonary artery wedge pressure > 15 mm Hg); stage 3: pulmonary vascular damage (systolic PAP ≥ 60 mm Hg, mean PAP ≥ 25 mm Hg, pulmonary vascular resistance > 3 Wood units; and stage 4: right ventricle, right atrium, or tricuspid damage (mean right atrial pressure > 15 mm Hg). Finally, a "combined cardiac damage staging system was created with stages 0, 1, and 2 assigned according to TTE and stages 3 and 4 assigned according to RHC, the latter being the decisive method in discordant cases. In both groups, TTE assigned most patients to stage 2 while RHC assigned to stage 1 or 3, and there was only moderate agreement between the 2 methods. Up to 50% of patients with stage 1 or 2 cardiac damage according to TTE were reclassified to stages 3 and 4 after RHC. Patients with discordant classification were older with a higher prevalence of atrial fibrillation, higher NT pro-BNP levels, and more pronounced signs of LV diastolic dysfunction at TTE. A significant increase in all-cause mortality with each stage of cardiac damage was observed in both groups with the use of either the invasive or the noninvasive staging method. The combined staging system showed a discrimination ability between stages 3 and 4 for predicting mortality that was better than TTE alone but similar to RHC alone. On the other hand, no patient with stage 0 cardiac damage at TTE was reclassified to stage 3 or 4. When the authors repeated the assessments for the time frame between the diagnostic workup until the AVR (23% of the patients with initial m/asAS and 49% of those with ssAS) they found a similar incremental prognostic value for each stage. Among the limitations associated with this study, in addition to the single-centre retrospective observational design, the number of patients included is relatively small considering that they are divided into 2 groups of 5 stages each. Furthermore, there were no differences in LV mass, LA volume, or systolic PAP between moderate and severe AS groups. Although valve crossing may not be necessary in patients with stage > 2 and may be harmful in all of them, it gives complementary information regarding aortic valve severity. It is unclear in how many cases the aortic valve was crossed, especially in patients with symptomatic moderate AS or TTE stage 0 or 1. The lack of this information raises the question of whether symptomatic patients with moderate AS had more severe AS that was underestimated. The Belmonte et al. study adds to the body of evidence advocating for the implementation of a more comprehensive approach in AS assessment, extending beyond the valve and the LV. The combined staging system proposed by Belmonte et al. can help identify patients with more advanced disease who would benefit from timely AVR. On the other hand, advanced cardiac damage staging, independently from its causal relation with AS, may help identify futility in elderly comorbid patients. Finally, combining TTE and RHC to assess cardiac staging was more accurate in predicting mortality than TEE alone. They have a complementary role in risk stratification for patients suffering from AS. Together they achieve more and it can be considered the best of both worlds. The authors have no funding sources to declare.