Cardiac damage staging in heart valve diseases. “Metastatic disease or synchronous neoplasms”

Abstract

The concept of cardiac damage staging in left-sided heart valve disease, adapted from the oncological approach, has been developed recently in order to improve the management of patients who may benefit from valve repair or replacement interventions. However, the cardiac damage is frequently not directly related to the valve disease, and cardiac and extra-cardiac non-valvular comorbidities influence the staging, unlike oncological staging where the associated damage all comes from the primary tumor. In practice, the cardiac damage classification is more an assessment of overall heart health than the direct consequences of valvular heart disease, and some cardiac damages are independent of the valve disease. Anyway, the cardiac damage staging remains a powerful predictor of outcome, especially after valve intervention. This viewpoint explores the concept of cardiac damage staging and the impact of the valve intervention on this classification.

Keywords

cardiac damage staging diagnosis and imaging heart valve disease surgical valve interventions transcatheter valve interventions

Introduction

The management and treatment of heart valve diseases have been revolutionized the last two decades due to an improved knowledge about the causes and evolution of these diseases, the optimization of the clinical follow-up, and the emergence of new therapies. However, despite these significant beneficial changes in patients’ care, medical or pharmacological treatments are often palliative when valvular disease is severe and symptomatic, and invasive or minimally invasive valve repair or replacement, such as percutaneous therapies, should be performed to reverse or slow down the clinical course of the disease. Surgical or percutaneous repair or replacement have therefore been developed to treat the valve dysfunction (stenosis or regurgitation or mixed disease), and improve the symptoms and prognosis of heart failure (HF) related to the heart valve disease. Despite the refinement of the techniques and the increasing experience of the operators, these (surgical or percutaneous) interventions are associated to significant potential complications.¹ Indeed, the occurrence of complications is usually more frequent as the disease is advanced and the patient harbors significant comorbidities. The Heart-Team was therefore adopted by physicians in order to assess individually the interventional risk and choose the best suitable options according to the valve disease and the patient, including the possibility of “palliative” care. Thus, the futility of the intervention in relation to the mid-term expected improvement of the patient status should be evaluated by the Heart-Team according to the prognostic perspectives. In this way, Généreux et al firstly introduced the cardiac damage staging for severe aortic stenosis (AS) in 2017,² and this concept has been applied these last years to the other heart valves diseases and in different clinical conditions (symptomatic or asymptomatic patients, patients referred to transcatheter or surgical intervention, …) (Table 1).^3–6

Table 1.

Definitions and Criteria Used for Cardiac Damage Staging in the Different Heart Valve Diseases.

			Stage or Group 0	Stage or Group 1	Stage or Group 2	Stage or Group 3	Stage or Group 4
Aortic Stenosis	Symptomatic Severe AS	Généreux et al ²	No Cardiac Damage 2.8%	LV Damage - Increased LV mass index* - E/e’ > 14 - LVEF < 50% 12.8%	LA or MV Damage - Indexed LA volume > 34 mL/m2 - Moderate-severe MR - Atrial fibrillation 50.8%	Pulmonary Vasculature or TV Damage - SPAP ≥ 60 mm Hg -Moderate-severe TR 24.9%	RV Damage - Moderate-Severe RV Dysfunction 8.7%
	Asymptomatic Moderate to Severe AS	Tastet et al ⁶	No Cardiac Damage 12.1%	LV damage- LV hypertrophy- LV diastolic dysfunction ≥ grade II- Impaired LV global longitudinal strain ≤15%- LVEF < 60%27.2%	LA or MV Damage- Indexed LA volume > 34 ml/m2- MR moderate or greater- Atrial fibrillation46.4%	Pulmonary Vasculature or TV Damage- SPAP ≥ 60 mm Hg- Moderate-severe TR2.0%	RV Damage or Subclinical HF- RV systolic dysfunction moderate or greater- Moderate to severe low-flow (SVi < 30 ml/m2)12.2%
Aortic Regurgitation	Moderate and Severe Aortic Regurgitation	Silva et al ⁹	No Cardiac Damage 14.0%	LV damage- Increased LV mass index*- LVEF < 50%21.5%	LA or MV Damage- Indexed LA volume > 34 mL/m2- Moderate-severe MR- Atrial fibrillation49.2%	Pulmonary vasculature or TV Damage- SPAP ≥ 60 mm Hg- Moderate-severe TR12.3%	RV Damage- TAPSE < 17 mm or S’ Tricuspid < 9.5 cm/s3.0%
Primary Mitral Regurgitation	Primary Severe MR with Surgery	Van Winjgaarden et al ³	No Extra Mitral Valve Involvement 34.1%	LV Involvement- LVESD ≥ 40 mm- LVESVi ≥ 30 ml/m2- LVEF ≤ 60%21.6%	LA Involvement- LA diameter ≥ 55 mm- History of atrial fibrillation19.2%	Pulmonary Vasculature or TV Damage- SPAP > 50 mm Hg- TR grade > 216.3%	RV Involvement- TAPSE ≤ 17 mm8.8%
	Primary Severe MR with TEER	Popolo Rubbio et al ⁴	No Cardiac Involvement 8.9%	Left Heart InvolvementLV Dilatation/Dysfunction:- LVESD ≥ 40 mm- LVESVi ≥ 30 ml/m2- LVEF ≤ 60%LA Involvement:- LA diameter ≥55 mm- History of atrial fibrillation52.4%		Right Heart InvolvementPulmonary Vasculature or TV Damage:- SPAP > 50 mm Hg- TR grade > 2+RV/PA Uncoupling:- TAPSE/SPAP < 0.307 mm/mm Hg38.7%
	Asymptomatic Moderate or Severe Primary MR	Bernard et al ¹⁰	No Cardiac Damage 10.9%	Mild LV or LA Damage- LVEDD > 55 mm- LVESD > 35 mm- Forward LVEF ≤ 60%- Indexed LA volume > 40 mL/m212.7%	Moderate LV or LA Damage- LVEDD > 60 mm- LVESD > 40 mm- Forward LVEF ≤ 50%- Indexed LA volume > 60 mL/m2- Atrial fibrillation58.9%	Pulmonary Vasculature or TV Damage- SPAP ≥ 50 mm Hg- ≥ Moderate TR11.2%	RV Damage- ≥ Moderate RV Dysfunction6.2%
Secondary Mitral Regurgitation	Secondary MR with TEER	Stolz et al ⁵	Not Applicable	LV InvolvementLVEDV ≥ 159 mLLVEF < 50%9.5%	LA Involvement- Indexed LA volume > 34 mL/m2- History of atrial fibrillation46.3%	RV Pressure/Volume Overload- SPAP > 65 mm Hg- TR ≥ 3+15.2%	Biventricular Failure- RVPAc < 0.274 mm/mm Hg29%

Legends: *(>115 g/m2 male; > 95 female g/m2). AS: aortic stenosis; LA: left atrium; LV: left ventricle; LVEDD: left ventricle end-diastolic diameter; LVEDV: left ventricle end-diastolic volume; LVEF: left ventricle ejection fraction; LVESD: left ventricle end-systolic diameter; LVESVi: left ventricle end-systolic volume indexed; MR: mitral regurgitation; RV: right ventricle; RVPAc; right ventricle pulmonary artery coupling; SPAP: systolic pulmonary artery pressures ; SVi: stroke volume index; TAPSE: tricuspid annular plane systolic excursion; TEER: transcatheter edge-to-edge repair ; TR: tricuspid regurgitation; TV: tricuspid valve.

Staging in heart valve disease

According to the current international guidelines,^7,8 the timing of intervention for severe heart valve disease is firstly guided by the presence of symptoms, and secondly by the assessment of significant consequences on the cardiac function or anatomy. The heart being composite of serially arranged cardiac chambers and valves, the presence of valve disease traditionally lead to dysfunction or dilatation of the upstream cardiac structures. Indeed, the presence of significant left ventricle (LV) systolic dysfunction, assessed by the LV ejection fraction (LVEF), is a key marker of the timing of intervention in AS, while the presence of significant increase in systolic pulmonary artery pressure (SPAP) is one of the criteria to be evaluated in the management of primary mitral regurgitation (MR).^7,8 Beyond the specific criteria to consider for valve intervention, the assessment of all cardiac consequences/damage related to valve disease is essential to determine the disease progression and its prognosis. Inspired by the oncologic staging approach, the cardiac damage classification in left-sided valve diseases is based on the extent of damage, with the higher stages, and thus most advanced diseases, when the damage involves the right-sided cavities or cardiac system. Typically, the most advanced stage 4 in the PARTNER 2 study (intermediate risk-patients with severe symptomatic AS) corresponds to patients with moderate-severe right ventricular (RV) dysfunction according the classification proposed by Généreux et al² Illustratively, the primary neoplasm is the aortic stenosis, and the stage is even higher when the secondary metastatic disease affects the LV, the left atrium (LA), and ultimately the RV at the highest stage (Figure 1). Despite some variations of the criteria according to the valve involved (aortic and mitral), the type of valve disease, and the population studied; the stage 0 is no cardiac damage, the stage 1 corresponds to damage limited to the LV, the stage 2 is related to damage affecting the LA, and the stages 3 and 4 are defined respectively by the presence of increased SPAP or significant tricuspid regurgitation and RV systolic dysfunction (Figure 1 and Table 1). The Table 1 shows the criteria and the classifications used in the different populations and valve diseases studied, with the corresponding patients’ distributions. In all populations and valve diseases (excepted in patients with primary severe MR referred for cardiac surgery), the stage 2 represents approximatively 50% of the populations studied (Table 1), even in asymptomatic patients with moderate or severe AS. In order to introduce more granularity in the classification, especially for asymptomatic patients, some authors have introduced new criteria to define each group, such as LV longitudinal strain for AS or multiple levels of LV size and function (LVEF) for primary MR (Table 1). When applied in various left-sided heart valve diseases and similarly to the oncologic staging, the classification in stages of cardiac damage is powerful in predicting the outcome, particularly after valve interventions.^2–6,9,10

Figure 1.

Cardiac damage staging and influence of other heart or extracardiac diseases/injuries on the classification.

Synchronous neoplasms and proportionality of damage

However, some significant differences between the oncologic and the cardiac staging should be highlighted, and the main is that cardiac damages are not necessarily directly related to the heart valve disease. Indeed, the cardiac damages may precede the development of the valve disease or evolve concomitantly (Figure 2). Dahl et al recently showed that cardiac damage is highly prevalent in patients with mild AS, without relationship between the degree of cardiac damage and AS severity, but the stage was associated with comorbidities.¹¹ In this retrospective study including 9611 patients with mild AS, 50% of the patients have been classified in the stage 2 according to the definition of Généreux et al. Interestingly, Seko et al applied the Généreux classification in a retrospective population of 1639 patients with hypertension but no significant valve disease, and found that half of the patients had cardiac damage and one quarter had at least a stage 2.¹² The staging classification was also associated with long-term outcomes in these patients with hypertension in a stepwise manner. The Figure 2 summarizes a 20-year follow-up of a patient with initial stage 2 and no aortic stenosis but hypertension. The patient developed primarily atrial fibrillation, initially paroxysmal then permanent, and secondarily diabetes and progressive aortic stenosis. The cardiac damage, and thus the stage, got worse during the follow-up with mainly right-sided HF despite a non-severe AS. However, finally the AS became severe (paradoxical low flow low gradient (LFLG) AS) and the patient underwent transcatheter aortic valve intervention (TAVI). However, the worsening of the cardiac damage was not necessarily related to the progressive AS, although the AS worsens the cardiac burden. In cardiac staging, the cardiac damages are frequently associated to other (cardiac) diseases or conditions than the valve disease itself (Figure 1), while in the oncologic staging the metastatic damages are directly related to the primary neoplasm. Classically, patients with LFLG AS harbor a higher burden of comorbidities and/or cardiac conditions, as coronary artery disease or cardiomyopathies for classical LFLG and hypertension or diabetes for paradoxical LFLG, compared to patients with high gradient AS. This may explain the increasing severity denoted by the cardiac damage staging in patients with LFLG compared to high gradient.¹³ Moreover, a recent analysis in PARTNER 2 and 3 showed that patients with more advanced stages were more likely to be older, male, have higher surgical risk scores, diabetes, chronic lung disease, prior myocardial infarction, prior coronary artery bypass grafting, and were more likely to be frail,¹⁴ suggesting a direct influence of the normal cardiac aging and the extra-valvular cardiac conditions on the cardiac damage classification. Thus, the cardiac damage classification is more an assessment of overall heart health than the direct consequences of valvular heart disease, but the staging remains strongly associated with increasing mortality risk and should probably be considered in the evaluation of the Heart-Team. The assessment should therefore try to differentiate damages proportional to severity and linked to valvular disease from that secondary to other comorbidities. The Figure 1 shows the other heart or extracardiac diseases / injuries not related to the valve disease influencing the cardiac damage staging.

Figure 2.

Twenty years follow-up of a patient with cardiac damage not initially related to valve disease but with progressive aortic stenosis.

Improvement of cardiac damage and futility

The benefit of valve intervention to reverse the cardiac damage remains uncertain in some patients. In a substudy of PARTNER 2 and 3 trials (1974 patients, 794 surgical aortic valve replacement and 1.180 TAVI), only 15.6%. of the patients had an improved stage at one-year post-intervention.¹⁴ The majority (57.9%) of the patients had the same stage pre- and at 1year post-intervention, and 26.5% had a deteriorated stage.¹⁴ However, a majority of patients had an improvement of the KCCQ status of at least 10 points in each subgroup (deteriorated stage: 66.2%, unchanged stage: 75.9%, improved stage : 84.3%).¹⁴ Stolz et al also reported a significant improvement of NYHA class at 2 years after transcatheter edge-to-edge repair for secondary MR in all baseline stages, but with less symptomatic improvement in higher stages.⁵ Thus, the treatment of the valve disease is adequate to improve the functional status but is not necessarily associated with long-term improvement of the baseline cardiac damage stage. Currently, the literature remains limited concerning this issue, and the predictors of improved stage post-intervention are unknown. In clinical practice, the global assessment by expert team remains the rule to determine the futility of the intervention in advanced stages, and aggressive management of cardiac comorbidities and conditions (hypertension, arrhythmia, significant ischemia, cardiac amyloidosis, volume overload…) is required to preserve the benefit of the valve intervention. In some cases, additional percutaneous therapy of secondary associated (mitral and tricuspid) regurgitation is useful to limit the cardiac burden if persistent after the index valve treatment.

Conclusion

The concept of cardiac damage staging in left-sided heart valve disease, adapted from the oncological approach, is a powerful predictor of outcome, especially after valve intervention. However, the approach may appear more complex than expected, as cardiac damage is frequently not directly related to the valve disease, and cardiac and extra-cardiac non-valvular comorbidities influence the staging, unlike oncological staging where the associated damage all comes from the primary tumor. In practice, the cardiac damage classification is more an assessment of overall heart health than the direct consequences of valvular heart disease, and some cardiac damages are independent of the valve disease and persist despite improvement in valve status. Thus, despite frequent significant functional status improvement, the stage is rarely significantly improved after the valve intervention. Aggressive management of other cardiac and extra-cardiac conditions and diseases is then required concomitantly to the valve intervention in order to limit the evolution of cardiac damage.

Footnotes

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Josep Rodés-Cabau reports institutional research grants and consultant/speaker fees from Edwards Lifesciences and Medtronic.

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