Factors associated with the development of severe mitral regurgitation in patients with heart failure

Abstract

Background

Patients with heart failure (HF) and severe mitral regurgitation (MR) have poor outcomes. Early identification could allow physicians to consider interventions that may improve outcomes. We identified factors associated with progression to severe MR in patients with HF.

Methods

A total of 11 521 patients with HF and MR were screened, out of which we identified 7391 patients with a clinical diagnosis of HF and at least two echocardiograms at least 6 months apart. We excluded patients without a documented severity of MR at initial (n=1840) or follow-up (n=960) echocardiogram and those with severe MR at initial echocardiogram (n=450). We evaluated factors associated with the development of either moderate to severe or severe MR using multivariable logistic regression analysis.

Results

A total of 7391 patients were included in the study, 4173 (56.5%) male, and median age 75 (IQR (IQR) 64–83). In total, 357 (4.8%) patients developed severe MR on the follow-up echocardiogram at a median of 1.4 years (IQR 0.9–2.4). In addition to baseline MR severity, atrial fibrillation (adjusted OR (aOR)1.52), ischaemic heart disease (aOR 1.44), hypertension (aOR 1.35) and higher left ventricular end-diastolic dimension (aOR 1.36 per 1 cm) were associated with increased progression to severe MR. Beta-blocker prescription was associated with reduced progression to severe MR (aOR 0.74).

Conclusions

We identified several factors associated with the progression to severe MR in patients with HF. This information could be used by clinicians to identify patients who require closer echocardiographic follow-up and access to appropriate early interventions.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Small studies have identified factors associated with progression of mitral regurgitation in primary mitral valve disease, but large studies in patients with heart failure and mitral regurgitation are lacking.

WHAT THIS STUDY ADDS

• In a cohort of 7391 patients with heart failure and serial echocardiograms from two sites, 4.8% of patients developed severe mitral regurgitation (MR) during 1.4 years of follow-up. In addition to baseline MR severity, the presence of atrial fibrillation, ischaemic heart disease, hypertension and higher left ventricular end-diastolic dimension was associated with increased progression to severe MR. Beta-blocker prescription was independently associated with reduced progression to severe MR.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Patients with risk factors for progression may benefit from more frequent echocardiographic follow-up.

Introduction

Chronic mitral regurgitation (MR) is a common cause of dyspnoea, orthopnoea and worsening exercise tolerance.¹ Severe MR is present in ~10% of patients with heart failure (HF),¹ where it can contribute to symptom burden. Valve intervention is generally recommended for patients with symptomatic severe MR or asymptomatic severe MR in the presence of ventricular dysfunction or dilation.¹

In patients with acute HF exacerbations and left ventricular dysfunction, moderate-to-severe MR is present in up to 40% of patients.² Patients with HF and severe MR are at significantly increased risk of all-cause mortality and HF hospitalisation compared with those without severe MR.^{2 3} In patients with HF and preserved ejection fraction (HFpEF), the Acute Decompensated Heart Failure Syndromes (ATTEND) registry found a higher risk of the combined endpoint (cardiac death, hospitalisation from worsening HF or mitral/tricuspid valve surgery) with a fourfold increase in risk for each grade increase in MR severity.⁴ While treatment with maximally tolerated goal-directed medical therapy (GDMT) is critical for managing HF with reduced ejection fraction (HFrEF),5,7 it is less clear whether this impacts progression of MR.⁸ However, early identification of severe MR could allow physicians to consider transcatheter edge-to-edge repair before excessive ventricular dilation or pulmonary hypertension develops.9,11

This study aims to identify factors that are associated with progression to severe MR in a cohort of patients with a clinical diagnosis of HF, which may allow physicians to tailor surveillance strategies in these patients.

Methods

Study population

The study cohort consisted of patients in Alberta over the age 18 with a hospital encounter (inpatient hospitalisation or emergency department visit) for HF, defined by ICD-10 code I50.x and at least two echocardiograms at least 6 months apart between 1 April 2008 and 31 March 2016.12,14 Patients who underwent cardiac transplant or left ventricular assist device implantation between the two echocardiograms were excluded (n=54), as were patients without severity of MR recorded at baseline (n=1840) or at follow-up (n=960). Finally, we excluded patients with severe or moderate-to-severe MR at baseline (n=450). The study was approved by the University of Calgary and University of Alberta Research Ethics Boards, including waiver of informed consent for use of retrospective data. The data utilised in this analysis can be made available on request after appropriate data sharing agreements are in place.

Data sources and elements

Baseline covariates including comorbidities and cardiovascular medication use were identified using Alberta healthcare administrative databases in the 12 months before the initial echocardiogram. Co-morbidities were identified using ICD-10-CA codes and case definitions previously validated in Alberta administrative databases.^{12 15} Similarly, hospitalisations between echocardiograms for HF or acute coronary syndrome were determined from administrative databases using validated ICD-10-CA codes.^{12 15} Medication use was defined as at least two dispensations in the time between the two echocardiograms and was identified using the pharmaceutical information network (PIN), which captures >95% of outpatient prescription dispensations in Alberta.¹⁶ Given the low usage rates in our cohort for angiotensin receptor blocker-neprilysin inhibitor (ARNI), ivabradine or sodium glucose cotransporter-2 inhibitors (SGLT2i) (given the time period of the study), these medications were not included in the study. Additionally, all were non-formulary with a requirement for special authorisation even after they were released and therefore may not have been adequately captured (for instance, if patients were given samples). Interventions between echocardiograms, including permanent pacemaker implantation, implanted cardioverter-defibrillator (ICD) with or without cardiac resynchronisation therapy (CRT), and CRT without ICD were determined using procedural codes.^{12 15} ICD with CRT could not be differentiated from ICD without CRT because they are captured with the same procedural code.

 Echocardiogram information was extracted from echocardiogram imaging databases at two tertiary care centres, the Libin Cardiovascular Institute (Calgary) and Mazankowski Alberta Heart Institute (Edmonton), which include both outpatient and inpatient echocardiograms. For the present study, we included the entire spectrum of patients with HF including those with HFrEF, HF with mid-range LVEF (HFmrEF) and HF with preserved LVEF (HFpEF). Moreover, patients with recovered ejection fraction (HFrecEF) were defined as those who previously had an EF of ≤40% but have improved EF to >40%.¹⁷ Moderate LV dilation was defined as left ventricular internal diameter end diastole (LVIDD) >63 mm in male patients or >57 mm in female patients.¹⁸

Severity of MR was captured using preset codes from the two echocardiogram databases that were assigned at the time of echocardiogram interpretation. While there were no set criteria applied in this retrospective analysis, reader interpretation of MR severity generally aligns with the American Society of Echocardiography criteria and incorporates MR quantitation when available.¹⁹

Outcomes

The primary outcome was development of severe or moderate to severe MR on the follow-up echo. We combined these two grades of severity, given the known difficulties discerning the two by transthoracic echo,²⁰ and to be consistent with randomised trials of TEER.¹⁰ Mild-to-moderate MR was included with moderate MR.

Statistical Analysis

Data are presented as frequencies and percentages for categorical variables, mean±SD for normally distributed continuous variables or median IQR for continuous variables with a skewed distribution. Categorical variables were compared using χ2 or Fisher exact test, where appropriate, while continuous variables were compared with t-test or Wilcoxon rank sum tests, as appropriate. The primary analysis was association with development of severe or moderate-to-severe MR, which was evaluated using univariable and multivariable logistic regression analyses. The multivariable model included age, sex, medical history, medication prescriptions between the two echocardiograms, device therapies, LVIDD, LVEF category and baseline MR category. In the multivariable analysis, site was incorporated as a random effect using a mixed effects regression model, and the time between echocardiograms was included as a covariate. To further evaluate the model, we developed a risk score for predicting development of severe MR using logistic regression models and patients from one site. We evaluated area under the receiver operating characteristic curve (AUC) for severe MR in the training site (Calgary) and held-out site (Edmonton). Finally, we evaluated the proportion of patients progressing to severe MR with 95% CIs calculated using the Wilson score interval for a binomial proportion.²¹ All tests were two-sided and a p value<0.05 was considered significant. Statistical analyses were performed using STATA V. 13 (StataCorp, College Station, Texas).

Results

Population characteristics

After exclusions, 7391 patients were included in the study. The median age was 75 years (IQR 64–83) and 56.5% were male. Characteristics of the study population are shown in table 1. Patients who developed severe MR were more likely to have a history of atrial fibrillation (58.3% vs 43.6%, p<0.001), hypertension (75.9% vs 68.0%, p=0.002) and ischaemic heart disease (57.4% vs 46.4%, p<0.001). Characteristics of patients stratified by change in MR grade are shown in online supplemental Table 1.

Table 1. Population characteristics.

	No progression to severe MR (n=7034)	Progression to severe MR (n=357)	P value
Age (years), median (IQR)	75 (64–83)	77 (67–84)	<0.001
Male, n (%)	3974 (56.5)	199 (55.7)	0.785
Comorbidities
Diabetes, n (%)	2579 (36.7)	113 (31.7)	0.055
Hypertension, n (%)	4781 (68.0)	271 (75.9)	0.002
Coronary artery disease, n (%)	3266 (46.4)	205 (57.4)	<0.001
Stroke/TIA, n (%)	642 (9.1)	33 (9.2)	0.925
Atrial fibrillation n, (%)	3063 (43.6)	208 (58.3)	<0.001
COPD, n (%)	1900 (27.0)	86 (24.1)	0.245
Cancer, n (%)	610 (8.7)	36 (10.1)	0.338
Medications
Beta-blockers, n (%)	5424 (77.1)	279 (78.2)	0.698
ACEi/ARB, n (%)	5555 (79.0)	285 (79.8)	0.739
MRA, n (%)	1675 (23.8)	95 (26.6)	0.227
Digoxin, n (%)	885 (12.6)	59 (16.5)	0.034
Diuretics, n (%)	4402 (62.6)	245 (68.6)	0.021
Nitrates, n (%)	2172 (30.9)	143 (40.1)	<0.001
Hydralazine, n (%)	379 (5.4)	23 (6.4)	0.401
Device implant
Permanent pacemaker, n (%)	339 (4.6)	25 (4.9)	0.744
ICD±CRT, n (%)	268 (3.7)	32 (6.3)	0.006
CRT without ICD, n (%)	31 (0.4)	6 (1.2)	0.031

Age, sex and comorbidities were determined at the time of the initial echocardiogram. Medications were determined based on dispensations between the two echocardiograms.

ACEi, ACE inhibitor; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; MRA, mineralocorticoid receptor antagonist; TIA, transient ischaemic attack.

Echocardiographic characteristics are shown in online supplemental Table 2. The time between the two echocardiograms was a median of 1.4 years (IQR 0.9–2.4). The median LVEF was 55% (IQR 36–55). The largest proportion of MR at the time of first echocardiogram for all patients was mild (39.6%), and this remained the case at the time of second echocardiogram (40.1%). However, in most patients (n=3720; 50.3%), the severity of MR changed between echocardiograms. Online supplemental Table 3 summarises MR grade at initial and follow-up echocardiogram.

Figure 1 outlines the distribution of MR severity at baseline and changes at follow-up. Most patients who progressed to severe MR demonstrated moderate MR at baseline (58.3%), which constituted 208 patients in total and 12.6% of the patients with moderate MR at baseline. However, 102 patients with mild MR and 47 patients with none/trace MR at initial echocardiogram also went on to develop severe MR on follow-up, representing 41.7% of all patients that progressed to severe MR.

Figure 1. The figure above shows different colours for patients with different degrees of mitral regurgitation at baseline and how they progress in severity of their mitral regurgitation on follow-up echocardiogram. Patients with trace or no mitral regurgitation at baseline were represented in green, patients with mild mitral regurgitation at baseline were represented in blue and patients with moderate mitral regurgitation were represented in orange.

Associations with severe MR

Table 2 summarises the associations with the development of severe MR in unadjusted and adjusted analyses. Multivariable results are shown in figure 2. In multivariable models, baseline MR severity was independently associated with progression to severe MR (mild: adjusted OR 1.90, 95% CI 1.33 to 2.71, p<0.001; moderate: adjusted OR 7.31, 95% CI 5.21 to 10.3, p<0.001). Other independent factors associated with progression to severe MR included atrial fibrillation (adjusted OR 1.52, 95% CI 1.19 to 1.94; p=0.001), hypertension (adjusted OR 1.35, 95% CI 1.01 to 1.80, p=0.043), ischaemic heart disease (adjusted OR 1.44, 1.13–1.83; p=0.004) and LVIDD (per cm adjusted OR 1.36, 1.16–1.59; p<0.001). Beta-blocker use was associated with a lower likelihood of progressing to severe MR (adjusted OR 0.74, 95% CI 0.56 to 1.00, p=0.046). Results were similar after further adjusting for HF admission or ACS between echocardiograms (online supplemental Table 4). Results were also similar when considering follow-up echocardiogram data (online supplemental Table 5). Follow-up LVIDD was associated with progression to severe MR (adjusted OR 1.66 per cm, 95% CI 1.42 to 1.93, p<0.001), as were beta-blocker use, MRA use, hypertension and atrial fibrillation.

Table 2. Associations with progression to severe mitral regurgitation.

	Unadjusted OR	P value	Adjusted OR	P value
Age (per 10 years)	1.15 (1.06–1.25)	0.001	1.04 (0.94–1.15)	0.411
Male	0.97 (0.78–1.20)	0.779	0.92 (0.72–1.17)	0.484
Diabetes	0.80 (0.64–1.01)	0.055	0.76 (0.59–0.98)	0.033
Hypertension	1.48 (1.16–1.90)	0.002	1.35 (1.01–1.80)	0.043
Ischaemic heart disease	1.56 (1.26–1.93)	<0.001	1.44 (1.13–1.83)	0.004
Stroke or TIA	1.01 (0.77–1.46)	0.941	0.95 (0.65–1.40)	0.812
Atrial fibrillation	1.81 (1.46–2.25)	<0.001	1.52 (1.19–1.94)	0.001
COPD	0.86 (0.67–1.10)	0.225	0.78 (0.60–1.02)	0.070
Chronic kidney disease	1.27 (1.03–1.57)	0.027	1.10 (0.87–1.39)	0.418
Beta-blocker use	1.06 (0.82–1.37)	0.648	0.74 (0.56–1.00)	0.046
ACE/ARB use	1.05 (0.81–1.37)	0.698	0.84 (0.62–1.13)	0.242
MRA use	1.16 (0.91–1.48)	0.227	0.9 (0.68–1.19)	0.468
Digoxin use	1.38 (1.03–1.83)	0.030	1.01 (0.74–1.39)	0.926
Hydralazine use	1.21 (0.78–1.87)	0.392	0.92 (0.57–1.48)	0.735
Nitrate use	1.50 (1.20–1.86)	<0.001	1.22 (0.95–1.57)	0.117
Diuretic use	1.31 (1.04–1.64)	0.021	0.99 (0.76–1.28)	0.925
Pacemaker implant	1.06 (0.70–1.61)	0.781	0.68 (0.38–1.21)	0.186
ICD±CRT implant	1.76 (1.21–2.57)	0.003	1.10 (0.65–1.85)	0.730
CRT without ICD	2.80 (1.16–6.73)	0.022	2.78 (0.99–7.82)	0.053
Initial LVEF>50%	Reference		Reference
Initial LVEF 40–50%	1.59 (1.20–2.10)	0.001	1.18 (0.87–1.6)	0.294
Initial LVEF<40%	1.43 (1.12–1.83)	0.004	0.78 (0.56–1.09)	0.149
LVIDD (per cm)	1.32 (1.18–1.47)	<0.001	1.36 (1.16–1.59)	<0.001
Initial MR - Trace/none	Reference		Reference
Initial MR – Mild	2.14 (1.51–3.03)	<0.001	1.90 (1.33–2.71)	<0.001
Initial MR – Moderate	8.59 (6.22–11.9)	<0.001	7.31 (5.21–10.3)	<0.001

The multivariable model included all the variables listed in this table with site incorporated as a random effect and time between echocardiograms as a covariate. Significant values shown in bold.

CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; LVIDD, left ventricular internal diameter end diastole; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; TIA, transient ischaemic attack.

Figure 2. Adjusted associations with the development of severe mitral regurgitation (MR). Significant associations are shown in bold. ACEi; ACE inhibitor, ARB; angiotensin receptor blocker, COPD; chronic obstructive pulmonary disease, CRT; cardiac resynchronisation therapy, ICD; implantable cardioverter-defibrillator, MRA; mineralocorticoid receptor antagonist, TIA; transient ischaemic attack.

We evaluated progression to severe MR as a function of baseline MR severity and risk factors for MR progression (atrial fibrillation, ischaemic heart disease and moderate ventricular dilation), with results in figure 3. In patients with less than moderate MR, patients with three risk factors had an almost ninefold increase in likelihood of developing severe MR compared with patients with no risk factors (9.1% vs 1.1%, p<0.001). Additionally, the risk was almost double for patients with more than one risk factor compared with those without in patients with moderate MR (15.6% vs 9.0%, p=0.007). Prediction performance for severe MR for the risk score is shown in online supplemental Figure 1. AUC was similar in both the training site (AUC 0.759, 95% CI 0.727 to 0.790) and external testing site (AUC 0.780, 95% CI 0.735 to 0.825, p=0.449).

Figure 3. Proportion of patients developing severe MR during follow-up as a function of baseline mitral regurgitation (MR) severity and risk factors (atrial fibrillation, ischaemic heart disease, or at least moderate ventricular dilation). Error bars reflect 95% CIs.

Discussion

We demonstrated in this large cohort of patients with HF that the development of severe MR over a relatively short period of time, just over 1 year, occurs in ~5% of cases. As expected, baseline MR severity was strongly associated with progression to severe MR. However, other factors were also associated with increased risk of progressing MR to severe, including atrial fibrillation, ischaemic heart disease, hypertension and ventricular dilation. We also found that beta-blocker use was associated with a lower likelihood of progressing to severe MR. Importantly, 41.7% of the patients that progressed to severe MR did not have significant MR at initial echocardiogram. Our results suggest that these factors may help physicians in identifying which patients would require closer follow-up for progression of MR.

 Previous studies (in primary MR) have suggested that the regurgitant volume progresses at a rate of 7.4 mL/year and effective regurgitant orifice at 5.9mm²/year.²² In contrast, in functional MR, severity is driven by changes in ventricular dilation and loading conditions such that MR may worsen or improve over time in response to those conditions rather than progressing at a fixed annual rate.²³ Consistent with this, we observed heterogeneity in our study with a small proportion of patients developing severe MR (4.8%) and a large proportion of patients experiencing a reduction in MR severity (21.0%). A number of mechanisms may contribute to mal-coaptation of the MV leaflets in secondary MR, including global ventricular dysfunction, displacement of the papillary muscles with tethering of the leaflets, dilation of the annulus and inadequate leaflet adaptation to ventricular or atrial enlargement.²⁴ In our study, we identified ventricular dimension at baseline as an important independent predictor of progression to severe MR. Similarly, follow-up LVIDD was associated with development of severe MR. Secondary MR stemming from LV dilation and systolic dysfunction, often with concomitant mitral annular dilation, is also a common consequence of ischaemic and non-ischaemic cardiomyopathies.²⁵ Interestingly, initial LVEF category was not associated with development of severe MR. While the reason for this is unclear, it may be that worsening MR leads to afterload reduction allowing for preserved LV emptying. Additionally, patients with HF recovered EF have significant reductions in ventricular dilation, which is known to be a major driver of progression²³ and may be diluting the risk from abnormal EF at baseline. Finally, it’s worth noting that use of beta-blockers was associated with a lower likelihood of progressing to severe MR, which may be a reflection of their known benefits with respect to ventricular remodelling²⁶ or in management of arrhythmias.²⁷ Additionally, utilisation of most medical therapies was higher in patients with improving MR grade. Similar findings would be expected with the use of ARNI^{6 28} or SGLT-2i.²⁹ However, these medications were not readily available for the majority of the time analysed or indicated for HF at that time. Patients with diabetes were also slightly less likely to develop severe MR during follow-up. This may be a reflection of a more restrictive phenotype³⁰ (with 9.0% having moderate ventricular dilation compared with 11.3% of patients without diabetes), more aggressive blood pressure management in patients with diabetes or a type 1 error. Beta blockers were also associated with improvement of MR during follow-up, which may be a reflection of their known ventricular remodelling benefit.

Previous studies have evaluated medical history factors associated with progression of MR severity. One of these studies specifically evaluated patients with mitral valve prolapse³¹ and the other evaluated patients with rheumatic heart disease.³² Importantly, both of these studies were significantly smaller (82 and 539 patients, respectively) than our study and included a primary valvular MR population. In atrial functional MR, female sex is associated with progression of MR, and absence of atrial fibrillation is associated with regression.³³ Diabetes and ischaemic heart disease have been associated with progression from atrial functional MR to combined atrial and ventricular functional MR.³⁴ It is notable that a significant proportion of patients (4.8%) in our study progressed to severe MR in such a short period of time (median follow-up 1.4 years). Among those patients, a significant proportion (41.7%) had mild or less MR at the initial echocardiogram. This highlights the potential importance of risk stratifying patients to identify those who may benefit from more frequent imaging, particularly among patients with less significant MR which may not be routinely followed. For example, among patients with less than moderate MR, those with three risk factors for progression had an almost ninefold increased risk of progressing to severe MR compared with patients with no risk factors. This information could also be used by clinicians to identify patients that may benefit from more aggressive risk factor control, including utilisation of beta-blockers, to reduce risk of progression. Ma et al showed that mitral annular dimension was associated with progression in patients with mitral valve prolapse.³¹ However, in the study by Gomes et al,³² age and left atrial volume were associated with progression of MR in that population. Atrial fibrillation was also associated with progression to severe MR in patients with rheumatic heart disease in the unadjusted analysis (HR 2.53, p=0.001), but not multivariable models (HR 1.56, p=0.205).³² This is consistent with our finding regarding the potential importance of atrial fibrillation in predicting development of MR severity.

Patients with HF and severe MR have a high mortality rate, despite GDMT, with 2-year mortality ranging between 34 and 46%.^{10 35} Mitral-valve surgery is curative for primary MR; however, in secondary MR, the decision to proceed with surgical intervention needs to be balanced against surgical risk.³⁶ Transcatheter approaches may be beneficial in selected patients, providing a reduction in mortality and HF hospitalisations.^{10 11} Since this approach works best before significant ventricular dilatation has occurred,³⁷ early identification is of critical importance. The features outlined in this study can help identify patients that would benefit from closer monitoring. This is particularly true for patients who had less than moderate MR severity at baseline (which constituted 42% of patients developing severe MR), where current guidelines recommend repeat echocardiography in 3 to 5 years.

Limitations

Our study should be viewed in the context of a few important limitations. It is derived from retrospective data, which has inherent limitations related to data availability and accuracy. There was no distinction in terms of aetiology of the MR, and it was a mix of primary and secondary MR. Similarly, we have no data on contributions from atrial or ventricular remodelling mechanisms in contributing to the MR. While this can be difficult to determine from TTE alone,³⁸ the cohort likely includes patients with primary, secondary and mixed MR. However, previous studies have suggested that functional MR makes up the majority (~80%) of patients with HF and severe MR.³⁹ Additionally, quantitative parameters of MR severity (such as effective regurgitant orifice) were not available in the majority of cases and therefore could not be considered in the analysis and, like any other assessment, it can be prone to inter-reader variability. That being said, the echocardiographic studies were completed in tertiary centres where standardised imaging protocols and interpretation practices are followed. The data also does reflect values which are routinely available in clinical practice, where MR severity quantitation may not be performed due to image quality. Stress echocardiography may also provide additional insights but was not performed in our cohort. We excluded patients without documentation of MR severity at the index or follow-up echocardiogram. The majority of these patients would be expected to have no MR, which may have led to an overestimate of the proportion of patients progressing to severe MR. We did not capture surgical interventions including mitral valve surgery. However, we would not expect this to be a common intervention in patients with moderate or less MR. We were not able to capture ARNI or SGLT2i prescriptions in our dataset. However, studies have shown that both ARNI^{6 28} and SGLT2i²⁹ help in reducing MR severity in patients with HFrEF and functional MR. Our results are still directly relevant to the large proportion of patients not receiving all four pillars of GDMT.⁴⁰ Additionally, we would anticipate that associations with medical history and left ventricle dilation would persist in patients receiving all four pillars. Finally, there may be some ascertainment bias, with patients who developed symptoms from severe MR having echocardiography sooner than would otherwise have been planned.

Conclusions

In summary, the development of severe MR is relatively common in patients with HF even during short follow-up. Initial severity of MR, atrial fibrillation, ischaemic heart disease, hypertension and left ventricle dilation can help identify patients at the highest risk of progression to severe MR. Physicians could potentially use these factors when identifying which patients require closer follow-up for progression of MR.

Data availability statement

Data are available upon reasonable request.