Mitral-specific cardiac damage score (m-CDS) predicts risk of death in functional mitral regurgitation: a study from the National Echo Database of Australia

Abstract

Aims

We set out to explore associations between a ‘mitral-specific’ cardiac damage score (m-CDS) and survival outcomes in mitral regurgitation (MR) and compare the performance of the m-CDS and an ‘aortic-specific’ CDS (a-CDS) in patients with MR within the large National Echo Database of Australia.

Methods

Among 620 831 unique adults investigated with echocardiography, there were 17 658 individuals (3.1%) with moderate or greater functional MR (aged 76±13 years, 51% female) who met inclusion criteria. A randomly selected cohort of 5000 of these patients was used to test seven different CDS models for prediction of subsequent all-cause mortality during an average 3.8-year follow-up. The best-performing CDS model in the derivation cohort was then applied to a validation cohort of the remaining 12 658 individuals (aged 76±13 years, 51% female).

Results

The best-performing m-CDS model stratified the full cohort into Stage 0: control (1046 patients, 8%); Stage 1: left atrial damage (3416 patients, 27%); Stage 2: left ventricular damage (3352 patients, 26%); Stage 3: right ventricular damage (1551 patients, 12%) and Stage 4: pulmonary hypertension (3293 patients, 26%). Increasing m-CDS stage was consistently and incrementally associated with both all-cause and cardiovascular mortality at 1 year, 5 years and all-time and remained so after adjustment for increasing age and severity of MR, with a ~35% increase in mortality for each increase in CDS stage (p<0.001).

Conclusion

A m-CDS was robustly and incrementally associated with short-, medium- and long-term risk of all-cause and cardiovascular mortality in patients with functional MR in this large registry study.

Correspondence to Dr David S Celermajer; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Staging systems that integrate the functional and anatomical cardiac consequences of a given valve disease assist clinicians in judging the true severity of valvular disease, prognosticating risk and appropriately timing interventions beyond the traditional assessment of the valve and related symptoms in isolation.

• Scoring of extravalvular ‘cardiac damage’ has demonstrated incremental benefit in assessing outcomes in aortic stenosis and the aortic-cardiac damage score (CDS) has been subsequently applied to small cohorts of patients with mitral valvular disease, though with inconsistent results.

• Our aim was to statistically derive a robust mitral-specific CDS (m-CDS) from a large real-world echocardiographic database and then test the prognostic ability of the m-CDS in predicting mortality risk.

WHAT THIS STUDY ADDS

• The m-CDS incrementally predicts mortality in mitral regurgitation; with each increase in m-CDS stage carried an additional ~35% risk of mortality.

• These broadly generalisable findings support the need to consider valvular disease as part of a system and not as an isolated abnormality.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Staging cardiac damage may assist clinicians in stratifying the risk of mitral regurgitation for individual patients, timing intervention and assessing prognosis.

Introduction

The timing of intervention for valvular heart disease requires striking a balance between maximising symptomatic and prognostic benefits with minimising periprocedural risk and the potential complications of intervention. Current guidelines for chronic degenerative mitral regurgitation (DMR) recommend valvular intervention when the disease becomes symptomatic or, in the absence of symptoms, when extravalvular complications of left ventricular remodelling, atrial fibrillation (AF) and/or pulmonary hypertension (PH) occur.^1–3 This is based on evidence demonstrating a poorer prognosis when these progressive effects of valvular dysfunction manifest.

Indications for intervention are more limited for functional mitral regurgitation (FMR); if not undergoing cardiac surgery for another indication, transcatheter mitral valve repair is recommended if symptoms persist despite optimal medical therapy in ‘COAPT-like’ conditions.¹

Regarding aortic valve disease, Genereux and colleagues⁴ have described a ‘cardiac damage score’ (CDS) that sought to stratify the survival impact of extra-valvular cardiac damage detected using echocardiography for patients with severe aortic stenosis (AS) from the PARTNER-2 trials and demonstrated incremental prognostic risk associated with an increasing CDS. This ‘aortic’ CDS (a-CDS) has subsequently been applied to symptomatic severe AS,⁵ low-flow, low-gradient AS⁶ and asymptomatic moderate to severe AS,⁷ demonstrating utility as a prognostication and risk stratification tool. It has also been applied to DMR,⁸ asymptomatic moderate or severe DMR⁸ and heart failure with reduced ejection fraction with FMR in patients undergoing transcatheter mitral edge-to-edge repair,⁹ however, with less consistently encouraging results. As AS and mitral regurgitation (MR) have substantially different pathophysiology, cause different progressive impacts on cardiac chamber size and function and consequently follow divergent natural histories, the same staging schema should therefore not be applied interchangeably to both diseases, as recognised by the COAPT investigators.¹⁰

Here we present the development and application of a specific mitral-CDS (m-CDS) to cases of significant FMR, identified from the National Echo Database of Australia (NEDA), to explore associations between the m-CDS and survival outcomes in FMR and compare the performance of the m-CDS and a-CDS in FMR.

Methods

Study population

The NEDA registry is a large, multicentre database containing demographic and detailed echocardiographic reporting data on a clinical cohort comprising 631 824 individuals aged >18 years investigated between July 1985 and May 2019. As reported in more detail previously,¹¹ individual records are linked to mortality data from Australia’s National Death Index, which includes the date and causes of death. All individuals were followed up from the date of their last echocardiogram to death or censorship in May 2019.

Ethics approval

The NEDA project has undergone extensive ethical review throughout each state and territory of Australia and by the University of Notre Dame Human Research and Ethics Committee (HREC). All research is governed by appropriate guidelines and the NHMRC statement on the ethical conduct of human research.

Subject selection

Subjects were excluded from primary analysis for any of the following prospectively defined exclusions (figure 1):

• Less than moderate MR.

• DMR (primary), defined by echocardiogram report text (‘string text codes’) listed in online supplemental table 1.

• Previous mitral valve replacement or documented severe AS.

• Incomplete data for left atrial (LA) dysfunction (LA size or cardiac rhythm), left ventricular (LV) dysfunction (LV size or LVEF) and right heart dysfunction (RV size or right ventricular systolic pressure).

Figure 1. Flowchart of study cohort selection and mitral-cardiac damage score staging.

Definitions

Echocardiographic cut-offs were taken from the 2015 American Society of Echocardiography (ASE) guidelines,¹² as listed in online supplemental table 2. Patients were classified according to ‘cardiac damage’, depending on the presence or absence of echocardiogram-detected extra-mitral features, as in previously published CDS analyses listed in online supplemental table 8 and defined below.

• No damage: control group with non-primary MR not meeting criteria for extra-mitral cardiac damage. This may include, for example, preserved LV function with mild regional wall motion abnormality or mild LA and LV dilatation without obvious DMR characteristics such as prolapse/flail.

• LA damage: at least moderate LA dilatation (LA indexed volume ≥42 mL/m²) or the presence of AF.

• LV damage: at least moderate LV dilatation (LV indexed volume ≥90 mL/m² in males or ≥71 mL/m² in females) or impairment (LV ejection fraction (EF) <52% in males or <54% in females)

• RV damage: at least moderate RV dilatation (by relative RV and LV size in A4C view or RV basal diameter >50 mm) or systolic dysfunction (qualitative assessment and tricuspid annular plane systolic excursion <15 mm)

• PH: at least moderate PH (systolic pulmonary artery pressure ≥50 mm Hg).

For example, if a patient had both moderate LA dilatation and LVEF 35%, they would be categorised as ‘LV damage’ as this is the highest CDS stage of which they fulfil one criterion.

To increase criterion validity and maintain consistency, moderate severity was used to define the presence of this specific type of ‘cardiac damage’, with the exception of LVEF. While even a mild reduction in LVEF in the setting of severe MR may signify important LV contractile impairment,¹³ the cohort was comprised of both moderate and severe MR. An EF of 55%–59% in the setting of moderate MR would not be labelled as LV dysfunction in clinical practice.

CDS models were prospectively defined using the following hierarchical stages listed below. LA damage was used for Stage 1 as this represents the earliest cardiac physiological consequence of MR, and the remaining Stages 2–4 were rearranged in each possible combination to produce seven different CDS models: Model 1 (Stage 1: LA damage, 2: LV damage, 3: PH and 4: RV damage), Model 2 (1: LA, 2: LV, 3: RV and 4: PH), Model 3 (1: LA, 2: RV, 3: PH and 4: LV), Model 4 (1: LA, 2: RV, 3: LV and 4: PH), Model 5 (1: LA, 2: PH, 3: LV and 4: RV), Model 6 (1: LA, 2: PH, 3: RV and 4: LV) and Model 7: a-CDS (1: LV, 2: LA, 3: PH and 4: RV). Model 7 was derived from the Genereux et al a-CDS.⁴ Using Model 1 as an example, a patient would be classified as Stage 1: LA damage if they had no LV damage, RV damage or PH; as Stage 2: LV damage if they had no PH or RV damage, etc.

Kaplan-Meier survival curves were used to compare the association between seven CDS models against all-cause mortality in a randomly selected derivation cohort of 5000 patients to assess which model demonstrated superior risk stratification by CDS stages. The best-performing model was then applied to a validation cohort of the remaining 12 658 patients to evaluate the association of the m-CDS stage with all-cause and cardiovascular mortality.

Statistical analysis

Continuous variables were presented as mean±SD or median and IQR based on their distributions and compared using unpaired two-sided Student’s t-tests. Categorical variables were presented as numbers and percentages and compared using the χ² test. Time-to-event data was analysed using the Kaplan-Meier method.

Annualised survival rates for all-cause and cardiovascular mortality according to m-CDS were derived in the cases with complete follow-up at 1-year, 3-year, 5-year and 10-year time points.

Unadjusted survival analysis was performed using Cox proportional hazards regression. A multivariate Cox proportional hazards model was then used to derive adjusted HRs for all-cause and cardiovascular mortality during follow-up, adjusted for those significant variables (taken as HR >1.2 with lower bound CI >1.0) identified from the univariate analysis. The strength of the association of the different models with Kaplan-Meier survival was compared with the log-rank (Mantel-Cox) χ² test. All analyses were performed with SPSS software V.24.0 (IBM Corp, Armonk, New York, USA) and two-tailed p values <0.05 were considered statistically significant.

Results

There were 17 628 individuals with moderate or greater FMR included in the m-CDS study population, with a mean age of 76±13 years, 51% female and a mean body mass index of 26±6 kg/m². Approximately 1/3 were in AF at the time of echocardiogram, the mean LVEF was 54%±18%, and 4/5 had moderate MR, while 1/5 had severe MR.

CDS modelling

Comparing the seven CDS models in the randomly selected derivation cohort of 5000 using the log rank test, Model 2 (Stage 1: LA>Stage 2: LV>Stage 3: RV>Stage 4: PH) demonstrated the best prognostic stratification of mortality risk in FMR, so was used as the ‘mitral-CDS’ (m-CDS) for subsequent analysis of the validation cohort (online supplemental table 3). The a-CDS (Model 7) showed the poorest discriminatory power in FMR of the seven models tested.

m-CDS stages

Of the 12 658 patients included in the validation cohort, at the time of the echocardiogram, 1046 (8%) patients were in Stage 0, 3416 (27%) were in Stage 1, 3352 (26%) were in Stage 2, 1551 (12%) were in Stage 3 and 3293 (26%) were in Stage 4 (table 1). The mean CDS for the entire cohort was 2.4±1.4. Rates of each individual cardiac damage component within each stage are presented in online supplemental table 5.

Table 1

Frequency of cardiac damage stages among validation cohort (n=12 658)

Stage/component of stage	Frequency, n (%)
Stage 0: control	1046 (8)
Stage 1: LA damage LA dilatation Atrial fibrillation	3416 (27) 3040 (24) 1263 (10)
Stage 2: LV damage LV dilatation Reduced ejection fraction	3352 (26) 1106 (9) 3150 (25)
Stage 3: RV damage RV dilatation RV dysfunction	1551 (12) 310 (2) 1364 (11)
Stage 4: pulmonary hypertension	3293 (26)

LA, left atrial; LV, left ventricular; RV, right ventricular.

Baseline characteristics

Baseline demographic and echocardiographic characteristics according to the CDS stage are presented in table 2. Higher CDS stage (Stages 2–4 vs Stage 0–1) was associated with increased age, male gender, moderate or severe TR, severe MR (vs moderate MR), lower EF, higher LV volume and higher pulmonary pressure.

Table 2

Demographic and echocardiographic data by cardiac damage score stage, validation cohort

	0: no damage, n=1046	1: left atrial damage, n=3416	2: left ventricular damage, n=3352	3: right ventricular damage, n=1551	4: pulmonary hypertension, n=3293
Age	72±15	77±12	75±13	75±12	79±11
Male	379 (36)	1236 (36)	1776 (53)	1139 (73)	1586 (48)
Female	667 (64)	2180 (64)	1576 (47)	412 (27)	1707 (52)
Body mass index	26±5	26±6	27±6	26±6	26±6
Atrial fibrillation	0	1228 (36)	982 (29)	581 (38)	1137 (35)
Left atrial volume index	29±14	61±25	41±12	47±19	55±50
Left ventricular end-diastolic volume index	79±25	80±27	124±49	140±65	118±61
Left ventricular ejection fraction	64±5	62±6	40±12	35±14	49±17
Pulmonary arterial systolic pressure	34±7	38±7	37±7	40±6	61±10
≥Moderate tricuspid regurgitation	455 (44)	2062 (60)	1779 (73)	1126 (73)	1750 (53)
Moderate MR	979 (94)	3104 (91)	2719 (81)	1286 (83)	2403 (73)
Severe MR	67 (6)	312 (9)	633 (19)	265 (17)	890 (27)

MR, mitral regurgitation.

Outcomes

All-cause and cardiovascular survival data for the validation cohort, stratified by each CDS stage, are shown in figure 2, online supplemental table 5 and figure 1a-d. There was a consistent and incremental relationship between increasing CDS stage and the occurrence of all-cause or cardiovascular death at 1 year, 5 years and all-time.

Figure 2. Survival curves for (a) all-cause mortality and (b) cardiovascular mortality for the validation cohort (n=12 658) by m-CDS, adjusted for age and mitral regurgitation severity. m-CDS, mitral-specific cardiac damage score.

Predictors of mortality

Univariate regression analysis identified the independent variables that were significantly associated with all-cause or cardiovascular death (online supplemental table 6); specifically, increasing age decile above 60 years, gender, severe MR (vs moderate MR), AF, reduced EF and increasing CDS stage. The strongest associations (HR>1.2) of increasing age, severe MR and CDS stage were used in the multivariate Cox regression analysis. Reduced EF demonstrated collinearity with CDS stages 3 and 4 and so was not included in the multivariate analysis. After multivariate adjustment, increasing CDS stage remained significantly associated with increasing all-cause mortality and cardiovascular mortality (table 3 and figure 2).

Table 3

Multivariate model: adjusted* HRs with 95% CIs versus CDS 0

	All-Cause mortality		Cardiovascular mortality
	HR (95% CI)	P value	HR (95% CI)	P value
Age (vs<60 years)
Age (vs <60 years) 60–70 years 70–80 years >80 years	1.6 (1.4 to 1.8) 2.6 (2.3 to 2.9) 4.1 (3.6 to 4.5)	<0.001 for all	1.4 (1.2 to 1.7) 2.2 (1.9 to 2.6) 3.7 (3.1 to 4.3)	<0.001 for all
Severe MR (vs moderate MR)	1.4 (1.3 to 1.5)		1.6 (1.5 to 1.8)
CDS stage (vs 0)
CDS stage (vs 0) Stage 1 Stage 2 Stage 3 Stage 4	1.2 (1.1 to 1.4) 2.0 (1.8 to 2.2) 2.2 (2.0 to 2.5) 2.7 (2.4 to 3.0)		1.5 (1.2 to 1.8) 2.8 (2.3 to 3.3) 3.1 (2.5 to 3.7) 3.8 (3.5 to 4.8)

*Adjusted for age, severe MR and CDS stage.

CDS, cardiac damage score; MR, mitral regurgitation.

Discussion

Here we present an analysis from the NEDA registry of 17 628 adult patients with at least moderate FMR, demonstrating robust and incremental associations between increasing m-CDS and both all-cause and cardiovascular survival over short-, medium- and long-term follow-up. A consistent and significant risk of mortality at each timepoint was shown to increment alongside increasing m-CDS, with each increase in CDS stage associated with an ~35% increase in risk of both all-cause and cardiovascular mortality. This association remained strongly present after adjustment for increasing age and MR severity, each independently associated with poor prognosis in MR.

Four prior studies have evaluated CDS in various MR cohorts. With regards to the studies of FMR, Singh et al demonstrated that the CDS was independently associated with all-cause mortality, driven by tricuspid valve or pulmonary artery vasculature involvement and RV involvement.⁹ Similarly, Cavalcante et al reported in the COAPT cohort that at least moderate pulmonary hypertension or right heart involvement was common (63%) and was associated with the worst prognosis in both guideline-directed medical therapy and transcatheter edge-to-edge mitral valve repair groups.¹⁰ The m-CDS we report here demonstrated significant stratification of all-cause and cardiovascular mortality risk after adjustment for age and MR severity for each stage, highlighting prognostic utility beyond the previously reported CDS models in MR^{8–10 14 15} (online supplemental table 9). We hypothesise that this is due to the ‘moderate’ cut-offs used to increase the criterion validity of each stage and to the statistical derivation of a robust and pathophysiologically consistent staging for cardiac damage in MR. Anatomically, the haemodynamic consequences of chronic FMR—whether due to primary atrial and/or ventricular disease—will serially affect the left heart before the right. The most advanced CDS stage of PH, defined by PASP >50 mmHg, reflects the failure of both left and right heart compensatory mechanisms to accommodate the supraphysiological haemodynamic load of significant mitral regurgitation, underlying why the best performing statistical model identified PH as the poorest prognostic indicator of the m-CDS.^16–18

Using solely ‘valve-centric’ measures to assess the impact of a specific valvular lesion on outcomes does not consider the importance of the rest of the heart. Staging the progressive cardiac damage associated with valvular dysfunction provides important information on the success or failure of physiological compensation, the degree of negative remodelling and the risk of mortality. While various scoring models have been tested in MR, rather than testing a hypothetical model, we instead defined the m-CDS through systematic derivation and subsequent validation in a large cohort, using simple-to-apply and routinely measured echocardiographic variables that may aid clinicians in risk stratification. The m-CDS should be subsequently tested prospectively in different MR cohorts to confirm our findings; however, the mounting evidence for staging extra-valvular damage certainly supports its clinical relevance in the management of MR.¹⁹

Limitations

The major limitation of the NEDA database is that clinical data, including comorbidities (ie, ischaemic heart disease, cancer, vascular disease and systemic inflammatory disease), pharmacological treatment, New York Heart Association functional class, heart failure hospitalisations or biochemical parameters, are not currently linked to echocardiographic and mortality data.

As data collection in the NEDA database began in 1985, many echocardiographic studies preceded the ASE/European Association of Cardiovascular Imaging guidelines on chamber quantification,¹² which recommended an increased focus on quantitative variables compared with previous recommendations.²⁰ As such, qualitative grading was used to define MR severity, as semiquantitative or quantitative measures of MR severity were available for ~10% of studies. While the use of quantitative measures in FMR has numerous limitations,^{21 22} ideally, MR severity should be assessed with both combined qualitative and qualitative data, where PISA is reliably measurable. Similarly, reported assessments of RV size and function were largely qualitative, as in other CDS studies.⁴ Subsequent studies should include combined quantitative and qualitative echocardiographic assessments for both valvular function and chamber quantification, and artificial intelligence machine learning could in the future be used in the application of modelling such as this to other large datasets.

As many centres contributed to echocardiographic data collection, there is a potential for lack of standardisation in measurement and reporting; however, we believe that these aspects were unlikely to have introduced any systematic biases and instead are more reflective of real-world echocardiographic imaging, improving the generalisability of these findings.

Cardiac rhythm was defined at the time of the echo study; thus, cases of paroxysmal AF that were in sinus rhythm at the time of the echo would not be defined as AF. This may underestimate the prevalence of AF in each group, though it is unlikely to cause important bias.

Despite these limitations, there are significant advantages to this ‘big data’ approach. The large number of cases (at over 17 000) is more than 10-fold the number reported in any other CDS study. This provides highly powerful prognostic information, which complements and therefore should be reviewed alongside smaller studies providing more granular clinical data.

Conclusion

The m-CDS was robustly, independently and significantly associated with short-, medium- and long-term risk of all-cause and cardiovascular mortality in FMR subjects in this large registry study.

This research received no grant from any funding agency in the public, commercial, or not-for profit sectors. The National Echo Database Australia was initially supported (database engineering and infrastructure costs) through unrestricted research grants from Actelion, Bayer and GlaxoSmithKline. It is also supported by National Health and Medical Research of Australia funding (Grant 1055214).

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

X @PlayfordDavid

Contributors AM, DSC and MKCN: study planning. AM: statistical analysis and manuscript preparation. All authors: manuscript review. DSC is the guarantor.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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