Abstract
The advent and success of transcatheter aortic valve replacement (TAVR) for the treatment of severe, symptomatic aortic stenosis (AS) has sparked a renewed interest in the disease process associated with the valve disorder. While it is evident that untreated AS is fatal, the progressive and cumulative effects of AS on the heart have only recently been studied in a widespread fashion, after the initial pivotal TAVR trials in the United States. From these data, a novel staging system has been developed to characterize the extent of cardiac damage caused by AS. This staging system facilitates risk stratification of patients with AS using echocardiographic data and measurements to derive an assessment of morbidity and mortality. After being successfully validated using outcomes from several TAVR trials, the model has now been extrapolated to patients with moderate AS and other cardiac valve disorders as well. In this review, we explore the origins of the cardiac damage staging system, its validation, and uses in various cardiac conditions.
Introduction
Aortic stenosis (AS) is the most common valvular disorder in the Western hemisphere. Over the past decade, technological advances in transcatheter aortic valve replacement (TAVR) have paved the way for the identification and treatment of more patients with the disease. The low morbidity and mortality associated with modern-day TAVR sparked a renewed interest in the pathophysiology of aortic valve disease, questioning the long-held belief that valve replacement should be delayed until patients are symptomatic with severe AS. , The treatment of younger patients and those with bicuspid AS with TAVR is yet another example of how treatment indications may continue to expand for this disease. Given the recent indication expansion for aortic valve replacement in patients with asymptomatic, very-severe AS, it is clear that our understanding of the disease is rapidly evolving. In the same light, TAVR and what we have learned from the procedure continue to challenge our current paradigms. As TAVR becomes safer and indications continue to expand, it is critical to ask whether the current framework by which we view AS must be revisited altogether.
While the clinical outcomes and natural progression of AS are well described, no two patients with the disease are alike. Furthermore, no two hearts with AS will react the same to the continuous pressure overload. The valve should not be viewed in isolation, as AS can have detrimental effects on not only the chambers of the heart but also the remaining valves and conduction system as well. In this review, we will define cardiac damage and dysfunction as a function of AS and outline how the stages of cardiac damage can be used to stratify a patient’s overall risk. Furthermore, we will discuss how new methods of assessing cardiac risk have paved the way for investigating the effects of aortic valve replacement on moderate AS and what ongoing clinical trials may help answer.
The Role of Cardiac Damage in Risk Stratification
Severe AS is present in 5% of patients over the age of 60. The current guidelines definitively support aortic valve replacement when the following criteria are met: a peak velocity across the aortic valve of 4.0 m/s, a mean transvalvular gradient of 40 mm Hg, and an aortic valve area of <1.0 cm 2 . , These parameters must be met with clinical symptoms related to AS, that is, dyspnea, heart failure, angina, or syncope, if no left ventricular (LV) dysfunction is present. When deciding on the appropriate treatment therapy for those with AS, a heart team approach is the preferred model to determine whether a patient should receive surgical aortic valve replacement (SAVR) or TAVR. Surgical risk is a large factor in this decision and relies mostly on the Society for Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score. The score comprises baseline demographic factors, comorbid conditions, the surgery itself, and immediate preoperative conditions of cardiogenic shock, recent myocardial infarction, and heart failure. The STS-PROM does have its limitations and fails to take into account factors that would elevate AVR risk, namely porcelain aorta and prior mediastinal radiation. In addition to the STS score, frailty assessments in elderly patients with severe AS have become more commonly accepted as a strong predictor of cardiac risk, driven by grip strength and 6-meter walk time assessments. ,
While comorbidity and frailty currently drive risk stratification, it is well accepted that baseline cardiac damage holds prognostic significance. Recent literature demonstrates that by the time symptomatic, severe AS is identified, the vast majority of patients will exhibit some degree of cardiac damage. The extent of cardiac damage, as it turns out, is a reliable means of prognostication and, thus, risk stratification for AVR.
A novel method of using stages of cardiac damage for risk stratification was first introduced by Genereux et al. in 2017. This approach was predicated on the fact that cardiac damage in a heart with AS would progress in a manner consistent with the physiologic effects of the obstruction. The LV would therefore be affected first, followed by progressive changes in the left atrium, pulmonary vasculature, and finally, right ventricle (RV). According to this model, patients can be stratified into one of 5 categories, based on index transthoracic echocardiogram, that is, prior to valve replacement. The stages, seen in Figure 1 , are as follows: stage 0: no other forms of cardiac damage identified; stage 1: LV damage (LV hypertrophy [LV mass index >95 g/m 2 for women, >115 g/m 2 for men], severe LV diastolic dysfunction [E/e′ >14], or LV systolic dysfunction [LV ejection fraction <50%]); stage 2: left atrial or mitral valve damage or dysfunction (left atrial enlargement [>34 mL/m 2 ], atrial fibrillation, or moderate or severe mitral regurgitation); stage 3: pulmonary artery vasculature or tricuspid valve damage or dysfunction (pulmonary hypertension [systolic pulmonary arterial pressure ≥60 mm Hg] or moderate or severe tricuspid regurgitation); stage 4: RV damage (moderate or severe RV dysfunction). If patients met criteria for multiple stages, they were assigned to the highest (worst) stage. This staging scheme has been tested against patients undergoing TAVR and SAVR across various studies, and its utility has been validated both before and after valve replacement.
In a subanalysis of the Placement of Aortic Transcatheter Valves (PARTNER) 2 trial, researchers sought to identify cardiac damage in enrolled participants. The design and results of the PARTNER 2 trial have been previously described. Briefly, 2032 participants with severe AS who were intermediate risk for SAVR were randomized to receive SAVR or TAVR with a balloon expandable valve.
At the time of baseline echocardiogram, only 2.8% of patients were classified as stage 0 (no cardiac damage). More than half (50.8%) of patients were in stage 2 (left atrium [LA] or mitral valve damage) and a quarter (24.8%) were in stage 3 (pulmonary vasculature or tricuspid valve damage). There was a substantial, statistically significant association of index stage of cardiac damage with all-cause death and cardiac death at 1 year, which increased with corresponding stages ( Figure 2 ). All-cause death occurred in 24.5% of participants in stage 4, 21.3% in stage 3, 14.6% in stage 2, 9.2% in stage 1%, and 4.4% in stage 0. After adjusting for all possible covariates, stage of cardiac damage was the strongest predictor of death and cardiac death of all baseline variables, such that there was an incremental increase in hazard ratio by 1.45 with each increase in stage. This novel classification was shown to be more predictive than frailty and chronic obstructive pulmonary disease, some of the strongest known predictors.
Interestingly, cardiac damage identified in patients was not necessarily cumulative or sequential from one stage to the next. The assumed natural progression of damage would affect the cardiac chambers in a retrograde fashion, wherein the LV is first affected, followed by the LA, pulmonary vasculature, and finally RV. In patients with stage IV cardiac damage and RV dysfunction, however, only 25% were found to have pulmonary hypertension and 75% LA dysfunction. While cardiac damage may be the consequence of disease other than the aortic valve itself (i.e., chronic obstructive pulmonary disease, coronary artery disease), these data suggest that individual environmental and genetic factors play a significant role in the development and expression of cardiac damage due to AS.
The role of cardiac damage in AS was further validated in a larger cohort of patients, using a pooled analysis of patients in the PARTNER 2 and PARTNER 3 (low-risk valve replacement) studies. Of the 3401 participants across the 2 studies, 1974 had echocardiographic data that was complete and able to be evaluated. Similarly, there were few patients without cardiac damage categorized to stage 0 (6.8%). Again, approximately half of patients were in stage 2 (51.4%), and almost a quarter of patients belonged to stage 3 (21%). Two-year outcomes were now measured, demonstrating the highest proportion of death in stages 4 and 3 (28.2% each), followed by stage 2 (14.6%), stage 1 (7.1%), and stage 0 (2.5%). A similar trend across the stages was noted for cardiovascular death and heart failure hospitalization at 2 years. These findings solidified the ability to stratify patients’ risk for valve replacement based on echocardiographic parameters.
Progression of Cardiac Damage After Valve Replacement
Whether AS-associated cardiac damage is reversible is yet to be determined. Despite a well demonstrated association between damage and risk of death, investigators sought to determine if replacing the aortic valve could revert a patient to a lesser stage and potentially decrease their risk of CV-associated mortality overall. Using a pooled cohort of PARTNER 2 and PARTNER 3 patients, echocardiograms were assessed at 1-year follow-up, and patients were recategorized by stages of cardiac damage. Compared to pre-AVR, 15.6% of patients improved at least 1 stage, 26.5% deteriorated by 1 stage, and 57.9% remained in the same stage. The individual components of each stage were also assessed: LA enlargement, LV mass, and tricuspid regurgitation were among the least likely to improve. Importantly, the stage of cardiac damage that patients fell into at 1 year remained a strong independent predictor of death and morbidity at 2 years. Regardless of index stage, patients who deteriorated had a much higher likelihood of death and heart failure hospitalization if they had a deterioration in stage rather than improving or remaining the same. Those in stage 1 at baseline, for example, had a 9.6% risk of death at 2 years when deterioration to stage 2 occurred, 3.5% if no change occurred, and 0% if improvement to stage 0 occurred.
Cardiac Damage Stages and Quality of Life
Extravalvular cardiac damage has an association with patient-reported outcomes as well. To assess this, patients enrolled in all 3 PARTNER trials were pooled, and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores were categorically evaluated by stage of cardiac damage. Out of 1974 patients with available echocardiograms, 1427 had both follow-up echocardiogram and KCCQ scores sufficient for analysis. At baseline, there was a significant decrease in quality of life with each increase in cardiac damage stage (stage 0: 65.6, stage 1: 60.6, stage 2: 58.4, stage 3: 49.6, stage 4: 47, p < 0.0001). When reassessed at 1-year postintervention, KCCQ increased by at least 20 points across each stage of cardiac damage in those who survived with a favorable outcome. Interestingly, the same graded decrease with each stage of cardiac damage held true at 1 year, with the highest KCCQ scores in patients who started out as stage 0, and the lowest in those with stage 4 (stage 0: 87.8, stage 1: 82, stage 2: 80.5, stage 3: 74.1, stage 4: 79.1). Interestingly, those with stage 4 reported the largest increase in quality-of-life score at 1-year, with a mean difference of 28.4 points on the KCCQ scale. These findings show that while all patients demonstrated an improvement of quality of life after intervention, patients with higher stages of cardiac damage at baseline may have the most room for improvement, and when they survive, do show improvements in KCCQ and stage of cardiac damage.
Validation of Cardiac Damage Stages
Since its association with mortality in the PARTNER trial was established, the stages of cardiac damage have been validated in several cohorts, including international registries and clinical trials. In total, these criteria have been applied to more than 40,000 patients undergoing cardiac procedures ranging from cardiac resynchronization therapy to surgical aortic valve replacement, all with similar findings in mortality across the board ( Table 1 ).
| First author, year | N | Study population | Modality used to characterize cardiac damage |
|---|---|---|---|
| Aortic stenosis | |||
| Genereux et al., 2017 | 1661 | Severe symptomatic AS undergoing TAVR or SAVR | TTE |
| Fukui et al., 2019 | 689 | Severe symptomatic AS undergoing TAVR | TTE |
| Vollema et al., 2019 | 1189 | Severe symptomatic AS | TTE |
| Tastet et al., 2019 | 735 | Moderate-severe asymptomatic AS | TTE |
| Berkovitch et al., 2020 | 2608 | Severe symptomatic AS undergoing TAVR | TTE |
| Maeder et al., 2020 | 421 | Severe AS with complete invasive hemodynamics obtained before AVR | Invasive hemodynamic assessment |
| Baz et al., 2020 | 94 | Severe AS undergoing TAVR | TTE and biomarkers |
| Vollema et al., 2020 | 616 | Severe symptomatic AS with available LV GLS | TTE |
| Lloyd et al., 2021 | 44 | Severe AS patients referred for TAVR with biomarkers assessment | TTE and biomarkers |
| Park et al., 2021 | 145 | Severe asymptomatic AS randomized to SAVR vs. clinical surveillance | TTE |
| Schewel et al., 2021 | 1400 | Severe symptomatic AS with invasive hemodynamic assessment before TAVR | Invasive hemodynamic assessment |
| Okuno et al., 2021 | 1133 | Severe AS undergoing TAVR | TTE |
| Amanullah et al., 2021 | 1245 | Moderate AS | TTE |
| Snir et al., 2021 | 12,013 | Severe AS | TTE |
| Okuno et al., 2021 | 1156 | Severe AS undergoing TAVR | TTE |
| Avvedimento et al., 2021 | 262 | Severe AS undergoing TAVR | TTE before and 30-d post-TAVR |
| Baz et al., 2021 | 224 | Severe symptomatic AS undergoing TAVR | TTE |
| Zhu et al., 2022 | 427 | Severe AS undergoing TAVR | TTE |
| Hirasawa et al., 2022 | 405 | Severe AS undergoing TAVR | Computed tomography |
| Shamekhi et al., 2022 | 933 | Severe AS undergoing TAVR | TTE |
| Gutiérrez et al., 2022 | 496 | Severe AS undergoing TAVR | TTE |
| Genereux et al., 2022 | 1974 | Severe symptomatic AS undergoing TAVR or SAVR | TTE before and 1-y post-TAVR |
| Aortic regurgitation | |||
| Silva et al., 2022 | 571 | Moderate-severe aortic regurgitation | TTE |
| Mitral regurgitation | |||
| Bernard et al., 2022 | 338 | Asymptomatic primary MR | TTE |
| Singh et al., 2022 | 325 | Secondary MR | TTE |
| Cavalcante et al., 2022 | 387 | Secondary MR | TTE |
| Shamekhi et al., 2022 | 929 | Patients undergoing TEER | TTE |
| Van Wijngaarden et al., 2022 | 1106 | Severe primary MR undergoing surgery | TTE |
| Tricuspid regurgitation | |||
| Dietz et al., 2020 | 1311 | Significant TR | TTE |
| Galloo et al., 2022 | 278 | Significant TR undergoing surgery | TTE |
| Hypertension | |||
| Seko et al., 2019 | 1639 | Patients with hypertension | TTE |
| Heart failure | |||
| Stassen et al., 2022 | 844 | Patients with heart failure undergoing CRT placement | TTE |
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