Authors: Victoria Delgado (1University Hospital Germans Trias i Pujol, Badalona, Spain.), Nina Ajmone Marsan (2Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.), Robert O. Bonow (3Northwestern University Feinberg School of Medicine, Chicago, IL, USA.), Rebecca T. Hahn (4Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA.), Russell A. Norris (5Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.), Liesl Zühlke (6South African Medical Research Council, Cape Town, South Africa.; 7Division of Paediatric Cardiology, Department of Paediatrics, Institute of Child Health, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.), Michael A. Borger (8University Department of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany.)
Categories: Article
Source: Nature reviews. Disease primers
Authors: Victoria Delgado, Nina Ajmone Marsan, Robert O. Bonow, Rebecca T. Hahn, Russell A. Norris, Liesl Zühlke, Michael A. Borger
Degenerative mitral regurgitation is a major threat to public health and affects at least 24 million people worldwide, with an estimated 0.88 million disability-adjusted life years and 34,000 deaths in 2019. Improving access to diagnostic testing and to timely curative therapies such as surgical mitral valve repair will improve the outcomes of many individuals. Imaging such as echocardiography and cardiac magnetic resonance allow accurate diagnosis and have provided new insights for a better definition of the most appropriate timing for intervention. Advances in surgical techniques allow minimally invasive treatment with durable results that last for ≥20 years. Transcatheter therapies can provide good results in select patients who are considered high risk for surgery and have a suitable anatomy; the durability of such repairs is up to 5 years. Translational science has provided new knowledge on the pathophysiology of degenerative mitral regurgitation and may pave the road to the development of medical therapies that could be used to halt the progression of the disease.
Mitral regurgitation is one of the most common valvular heart diseases worldwide and is characterized by a failure of mitral valve leaflet coaptation that causes blood backflow from the left ventricle to the left atrium^1^ (Fig. 1). In degenerative mitral regurgitation, the mitral leaflet coaptation failure is caused by direct damage to the mitral valve apparatus, which appears characteristically with myxomatous, excessive and redundant mitral leaflets and chordae tendineae leading to excessive motion (beyond the mitral annulus into the left atrium) of one or more segments of the mitral leaflets or is due to thorn chordae tendineae resulting in flail leaflet. These features permit differentiating degenerative mitral regurgitation from other aetiologies of primary mitral regurgitation, such as rheumatic heart disease (where the damage consists of thickening of the mitral leaflets, chordae tendineae and subvalvular apparatus leading to restriction of leaflet motion in systole and diastole) or left ventricular or left atrial dilatation that separates mitral leaflets that appear structurally normal.
The treatment of degenerative mitral regurgitation is based on its severity, the presence of symptoms, the haemodynamic consequences on the cardiac chambers and pulmonary circulation, and the probability of performing an effective and durable mitral repair (surgically or with transcatheter techniques) or mitral valve replacement^2,3^. The lifetime management of patients is an important consideration in the decision-making, and guidelines consider patient age and comorbidities that may influence prosthetic valve durability, and patient expectations^2,3^. Transcatheter therapies are safe and feasible alternatives in patients at high operative risk or with contraindications to surgery. Ongoing trials will determine whether these therapies are efficacious in patients at lower operative risk^4^. New imaging techniques — such as three-dimensional echocardiography and cardiac magnetic resonance (CMR) imaging — have provided important new insights into the pathophysiology and risk stratification of patients with degenerative mitral regurgitation and help in decision-making^5,6^.
This Primer provides an up-to-date overview of the epidemiology of degenerative mitral regurgitation, novel pathophysiological concepts that may pave the road to the development of preventive therapies, and a critical appraisal of the role of new imaging modalities in diagnosing patients with degenerative mitral regurgitation and deciding the timing and mode of treatment.
Degenerative mitral regurgitation affects at least 24 million people worldwide, with an estimated 0.88 million disability-adjusted life years and 34,000 deaths in 2019 (ref. 7). Degenerative mitral regurgitation is defined as myxomatous degeneration of the mitral valve leading to regurgitation or prolapse^1^. The most frequent form of degenerative mitral regurgitation is mitral valve prolapse that is characterized by the presence of a single segment of the anterior or posterior mitral leaflet with excessive motion during systole exceeding the mitral annulus plane and entering the left atrium^1^. When there are two or more prolapsing segments of the mitral leaflets, the mitral valve shows excessive, redundant leaflet tissue and is called Barlow disease (Fig. 1).
The prevalence of degenerative mitral regurgitation has increased by 70% over the past ~20 years, reaching 18.1 million cases in 2017 with little change in the age-standardized prevalence and a 32% reduction in age-standardized mortality (35,700 deaths in 2017)^8^. Population growth and ageing are associated with this increase in prevalence^1^. Regional disparities in survival, treatment and outcomes need to be addressed, however, and access to echocardiography, surgical or transcatheter valve repair or replacement need to be urgently improved, especially in low-income and middle-income countries. There are large geographical differences in the prevalence of degenerative mitral regurgitation, with the highest prevalence in countries with the highest sociodemographic indexes^1^. However, there is less geographical variation in terms of mortality rate in degenerative mitral regurgitation, suggesting that this disease is more independent of traditional atherosclerotic risk and may be less influenced by modifiable factors^9^.
A comprehensive understanding of valve development and normal valve structure is integral to the recognition of degenerative mitral regurgitation. The mitral valve apparatus has a very complex structure designed to withstand the otherwise damaging mechanical forces of a beating heart. An important component of this apparatus are the mitral valve leaflets, which, when mature, present scant cellularity and consist of three distinct layers of extracellular matrix with specific composition and biomechanical (1) the ventricularis (or fibrosa) composed primarily of collagen type I, and able to face the high pressures present in the left ventricle; (2) the spongiosa, rich in proteoglycans that is crucial for water retention and to resist the compressing forces of leaflet coaptation; and (3) the atrialis, abundant in elastin and lamellar collagen to sustain the stretch during systole and recoil during diastole^10^. The mitral valve leaflets are enclosed by valvular endothelial cells (VECs)^11^, which sense the haemodynamic environment, and interspersed with valvular interstitial cells (VICs), which are responsible for the maintenance of the extracellular matrix^12^. The VICs and VECs are unique to cardiac valves, with reciprocal interaction and a specific plasticity (that is the ability to change phenotype and behaviour in response to molecular triggers and mechanical stress)^13^. Crucial components of the mitral valve apparatus are also the annulus, chordae tendineae, papillary muscles and associated regions within the left ventricle. Any defect that may alter the correct development of one or more of these structures, or any lesion that may modify their response to stresses will have significant impact on valve function and durability (Fig. 2).
In degenerative mitral regurgitation, a common structural hallmark is the altered organization of the extracellular matrix^14^ (Fig. 3). Degenerative mitral regurgitation can be differentiated into fibroelastic deficiency and myxomatous degeneration. In fibroelastic deficiency, the mitral valve leaflets are characterized by an extracellular matrix deficient in elastin, collagen and proteoglycans, except for the prolapsing or flailing scallop, which shows myxomatous degeneration^15^. In myxomatous degeneration (so-called Barlow disease), all the segments of the leaflets show increased thickness due to the expansion of the spongiosa by accumulation of amorphous extracellular matrix rich in proteoglycans, together with disruption of the elastin sheets and the collagen in the atrialis and vetricularis^16^. The formation of a fibrous layer (‘callus fibrosus’) at the atrial and/or ventricular side of the mitral valve leaflet is also responsible for leaflet thickening, but has only recently been described as being superimposed on the original leaflet^17^. This superimposed tissue is hypothesized to result from an increased leaflet stress and abnormal leaflet contact, playing an important role particularly in the progressive degenerative changes observed in adult valves.
Despite these observations, the underlying mechanisms of degenerative mitral regurgitation remain elusive, and only a few insights into the molecular mechanisms of myxomatous degeneration have been unravelled. The development of medical treatments possibly targeting the progression of such degenerative processes has therefore been significantly hampered.
Genetic discoveries based on familial and population studies in degenerative mitral regurgitation have revealed developmental origins of the disease. However, biological processes such as inflammation, intrinsic to the valve or paracrine from the left ventricle, and mechanical stresses also have a crucial influence on the pathogenesis and progression of degenerative mitral regurgitation.
Degenerative mitral regurgitation has also been described in syndromic diseases such as Ehlers–Danlos syndrome, Marfan syndrome, Loeys–Dietz syndrome, pseudoxanthoma elasticum and osteogenesis imperfecta, in which gene variants in collagens or components of the TGFβ pathway have been defined^18–20^. The genetic underpinnings of the non-syndromic forms of degenerative mitral regurgitation had remained largely unknown until recently, when a few genes were identified in studies in multiple families with degenerative mitral regurgitation and include FLNA^21,22^, DCHS1 (ref. 23), DZIP1 (ref. 24), PLD1 (ref. 25) and ADAMTS19 (ref. 26). In addition, population approaches through complete genome-wide association studies have identified distinct loci and established putative polygenic risk scores for degenerative mitral regurgitation^27,28^.
In all cases to date, genes associated with degenerative mitral regurgitation have been found to be expressed during valve morphogenesis, but many of them may also be functionally linked to how the valve responds to mechanical stimuli. These data strongly support a mechanomolecular link that integrates genetics, development and mechanobiology as part and parcel of normal structural development of the valve. How these signals integrate to form the stratified extracellular matrix are poorly understood, but probably stem from unique anatomical aspects of mitral valve morphogenesis. Therefore, to understand how degenerative mitral regurgitation occurs, one must initially recognize how a normal valve develops.
At its most rudimentary, valve morphogenesis goes through three major pre-endothelial to mesenchymal transformation (pre-EndMT), EndMT and post-EndMT remodelling^29–31^. In the earliest phase of the primitive valve, the endocardial cushion is filled with proteoglycans and is encapsulated by a uniform endocardium. During EndMT, a subpopulation of endothelial cells transform into migratory mesenchyme in response to various myocardium-produced growth factors. The mesenchymal cells invade the proteoglycan-rich environment of the endocardial cushion and are induced to proliferate. Defects in the pre-EndMT and EndMT phases result in impaired mesenchyme formation and/or proliferation and are generally not compatible with embryonic growth and viability. During the third phase of valvulogenesis (post-EndMT), the valve undergoes a differentiation and remodelling phase, which culminates in the final stratified valve structure including the definitive atrialis, spongiosa and ventricularis^30,32^. Within the tissue, interstitial cell proliferation decreases, but following a design that is largely unknown, all interstitial cells end up within distinct anatomical positions within the valve. These anatomical zip codes define the stratified make-up of the mitral valve while establishing functional relevance to the zonal boundaries within the tissue. As stated above, each of the genes identified in cases of degenerative mitral regurgitation can be linked to some aspect of mechanical regulation, which can also dictate how the cells change their position and function based on their microenvironment. Beyond the genetic data, this concept is also supported by the observations on the formation of chordae tendineae, which occurs precisely at the same time as the presence of collagen-secreting cells within the ventricularis. The spatiotemporal correlation between chorda formation, induction of collagen synthesis and cellular alignment suggests that tethering and mechanical gradients dictate how valve architecture is established^33,34^.
Considering all these developmental aspects, any defects within this complex temporospatial process alter the structure of the mitral valve and lead to progressive changes that result in a valve pathology over time. Therefore, structural and functional valve alterations that present in postnatal life can progress into degenerative changes in adult life. These may occur most probably in response to the continuous mechanical stress the valve is subjected to, and potentially other triggers such as inflammation. For example, initial evidence has been published indicating that superimposed tissue formation is induced by increased mechanical stress and is characterized by breakage of the VEC lining, and activation, proliferation and migration of existing VICs through this lining, forming the superimposed tissue and producing extracellular matrix; also the presence of macrophages has been demonstrated within the superimposed tissue, suggesting a possible pathogenetic role also for inflammation^35^.
Concomitantly with leaflet alterations, significant mitral valve annular abnormalities are also observed in patients with degenerative mitral regurgitation, including annular dilatation and disjunction, described as a separation between the left atrial wall at the level of the mitral valve junction with the left ventricular free wall^36^ (Fig. 4). These anatomical annular alterations lead to an abnormal annular displacement, pulled outward at late systole with a so-called functional prolapse, but also to significant annular flattening, which is believed to increase the stress applied to leaflets and chordae tendineae^37^. This increased stress possibly leads not only to progression of leaflets and chordal adverse remodelling, but also to secondary myocardial abnormalities. The observation that myocardial replacement fibrosis is frequently present in patients with degenerative mitral regurgitation, specifically in segments adjacent to the posteromedial papillary muscle and the mitral valve annulus, supports the hypothesis that a mechanical trigger (pulling of the elongated chorda and hyperdynamic annular motion and disjunction) is behind the development of myocardial abnormalities in these patients^38,39^. However, a primary concomitant mild cardiomyopathy has also been suggested to be part of the phenotype of some forms of degenerative mitral regurgitation (for example, in Barlow disease) based on the reported association with mutations in cardiomyopathy genes^40^, and also on the frequent observation of a disproportionate dilatation of the left ventricle (and of the left atrium) according to the severity of mitral regurgitation^41^.
The presence of severe mitral regurgitation portends a volume overload of both the left ventricle and the left atrium, which respond with an adaptive dilatation, in most cases first of the left atrium and then of the left ventricle. As a result, cardiac output is maintained, left ventricular ejection fraction is preserved or supranormal (as blood is pushed into a low-resistance chamber) and pulmonary pressures remain within normal limits. How long a patient with severe mitral regurgitation may remain in this ‘compensated’ phase varies substantially, and the time and the trigger for the occurrence of maladaptive changes of the cardiac chambers is still not well understood. It is has been shown that a chronic increase in left ventricular wall stress may lead to myocardial reactive fibrosis, microvascular ischaemia and cell death, with therefore subsequent myocardial replacement fibrosis^42–44^. These ultrastructural alterations result in myocardial initially subtle myocardial dysfunction difficult to diagnose by conventional diagnostic testing, and in late stages as an overt decrease in left ventricular ejection fraction and the occurrence of heart failure symptoms^45^. The latter are therefore considered a crucial indication for mitral valve intervention, since they represent important signs of secondary myocardial damage that could become substantial and irreversible and should be prevented by correcting the volume overload^2,3^. Heart failure symptoms could be also related to a further upstream effect of severe mitral regurgitation on the pulmonary circulation, with elevated pulmonary pressures reflecting the exhaustion of the left ventricle and left atrium compensatory mechanisms. Elevated pulmonary pressures can also induce right ventricular dilatation, secondary tricuspid regurgitation and ultimately right ventricular dysfunction, phenomena that represent a very advanced stage of the disease^46^.
Understanding the haemodynamic consequences of severe mitral regurgitation, and recognizing the initially adaptive and later maladaptive chamber remodelling secondary to the volume overload, is therefore crucial also for the clinical management of these patients.
The nature and severity of symptoms in patients with mitral regurgitation that prompt diagnosis are combinations of interrelated factors including the severity of regurgitation, its rate of progression (acute onset of severe mitral regurgitation versus chronic development of severe mitral regurgitation), the pressure within the left atrium and pulmonary venous and arterial vasculature, the presence of episodic or chronic atrial tachyarrhythmias, and the presence of associated valvular, myocardial or coronary artery disease.
Typical symptoms of degenerative mitral regurgitation include dyspnoea (shortness of breath) from increases in left atrial and pulmonary pressures, and fatigue and reduced exercise capacity from reduced cardiac output. Many patients with severe degenerative mitral regurgitation remain completely asymptomatic, although close questioning of the patient or the patient’s family might reveal subtle reductions in functional capacity. The onset of symptoms can be acute in those with an acute flail or ruptured chordae.
Classic auscultatory findings in patients with degenerative mitral regurgitation include a non-ejection apical systolic click that can precede a late systolic murmur. An anteriorly directed mitral regurgitation jet owing to posterior prolapse can create a systolic murmur which radiates to the left sternal border, and that can often be mistaken for aortic stenosis. The murmur shows little change, even in the presence of large beat-to-beat variations of left ventricle stroke volume, similar to the finding in atrial fibrillation, which contrasts with other causes of mid-systolic (ejection) murmurs, such as aortic stenosis, which vary greatly in intensity with stroke volume and therefore with the duration of diastole. Little correlation has been found between the intensity of the systolic murmur and severity of mitral regurgitation. In patients with a posteriorly directed mitral regurgitation jet, the murmur radiates to the axilla or occasionally to the spine. Auscultation during positional changes or the Valsalva manoeuvre can be quite helpful in detecting the mitral regurgitation murmur.
Among the various imaging diagnostic tests, echocardiography has a central role in the diagnosis of degenerative mitral regurgitation and provides information on aetiology and potential for repair, and severity and haemodynamic consequences (left ventricular systolic function, severity of dilatation of the left ventricle and left atrium, pulmonary pressures and right ventricular function).
Guidelines from the European Association of Cardiovascular Imaging and American Society of Echocardiography provide in-depth coverage of multimodality quantification of mitral regurgitation severity^47,48^. Grading degenerative mitral regurgitation with echocardiography relies on a multiparametric integrative approach that includes qualitative, semiquantitative and quantitative parameters. Qualitative parameters include valve lesions (flail leaflet) or the area of the left atrium occupied by the mitral regurgitant jet on colour Doppler, whereas semiquantitative parameters include the vena contracta of the regurgitant jet (the narrowest flow diameter at the level of the regurgitant orifice) and reversal of the systolic pulmonary vein flow. Quantitative parameters include the effective regurgitant orifice area and the regurgitant volume calculated based on the proximal isovelocity surface area method (summarized in current guidelines)^47,48^. These parameters may be discordant and hinder diagnosis of severe mitral regurgitation. Transoesophageal echocardiography may be needed in addition to transthoracic echocardiography for assessment of the detailed anatomy of the mitral valve, and to identify the mechanisms and severity of mitral regurgitation in some patients in whom the transthoracic echocardiography is inconclusive^49^. In addition, transoesophageal echocardiography is useful in determining whether optimal results can be achieved with surgical or transcatheter mitral valve repair, or whether mitral valve replacement is necessary^49,50^. For example, transcatheter mitral valve repair is technically challenging in mitral regurgitation due to Barlow disease or when the mitral leaflets are thickened and with calcifications in the grasping area. These aspects can be characterized by transoesophageal echocardiography better than with transthoracic echocardiography. 3D imaging and 3D colour Doppler echocardiography help elucidate the mechanism of mitral regurgitation^5,6^.
As patients with degenerative mitral regurgitation often present with dyspnoea on exertion, assessment of mitral regurgitation severity and pulmonary artery systolic pressure during exercise is useful since symptomatology is correlated with disease severity^51^. Exercise echocardiography is useful in patients with symptoms and mild or moderate mitral regurgitation at rest, and in patients who deny symptoms but who have severe mitral regurgitation on diagnostic testing. Thus, exercise testing is used to determine the load dependency of the disease and serves as an objective tool to evaluate symptoms. Particularly helpful to evaluate the load dependency of the disease is the observation that late-systolic mitral regurgitation becomes more holosystolic (that is, occurring throughout systole) with exercise, particularly if pulmonary arterial pressure rises significantly. By contrast, dobutamine stress echocardiography has little role in assessing degenerative mitral regurgitation.
CMR imaging is useful for quantification of mitral regurgitation when echocardiographic assessment is inconclusive, and is also the most accurate method for evaluating changes in left ventricular size, mass and function, and to determine left atrial size and function^42–44,47,48^. Quantification of mitral regurgitation with CMR imaging can be performed by various methods, although phase-contrast CMR imaging is the sequence of choice. Regurgitant volume and regurgitant fraction can be calculated by comparing the left ventricular stroke volume (obtained by planimetry of the short-axis cines) to the forward flow through the aortic valve (measured on phase-contrast CMR imaging).
Cardiac CMR imaging can also help identify the aetiology of mitral regurgitation and morphology of the leaflets and surrounding structures^52^. A recent study evaluating concordance between echocardiography and CMR imaging in detecting severe mitral regurgitation in asymptomatic patients with degenerative mitral regurgitation found discordance in 24% of patients, particularly in those with late-systolic and multiple regurgitant jets^53^. Patients with moderate mitral regurgitation based on echocardiography but with severe mitral regurgitation based on CMR had a worse outcome than patients with a concordant diagnosis of severity by both techniques. Since the availability of CMR imaging is relatively limited, this technique is usually requested in patients with severe mitral regurgitation and inconclusive echocardiographic findings to decide the management.
Although screening of the general population indicates that many individuals with degenerative mitral regurgitation have few clinical symptoms^54^, in large clinical populations the disease is strongly associated with heart failure, the need for valve surgery, the development of atrial fibrillation and increased mortality^55,56^. In one community-based study in 833 asymptomatic patients with degenerative mitral regurgitation, The 10-year all-cause mortality was 19 ± 2% and cardiovascular mortality was 9 ± 2%^55^. This increased mortality seemed to be related to the quantitative severity (evaluated by echocardiography) of mitral regurgitation (adjusted HR 1.15, 95% CI 1.10–1.20; P < 0.0001 per 10 mm^2^)^57^.
In chronic severe mitral regurgitation, the left ventricular end-diastolic volume increases, resulting in increased systolic left ventricular wall stress, which is a stimulus for eccentric hypertrophy. This left ventricular remodelling results in reduced afterload which, initially, is associated with increased ejection fraction. However, prolonged haemodynamic overload ultimately leads to myocardial decompensation, increased left ventricular end-diastolic pressure and, eventually, decreased left ventricular contractility, despite modest decreases in left ventricular ejection fraction.
In a long-term follow-up study in 1,875 patients with moderate or severe degenerative mitral regurgitation (specifically with flail mitral valve which consists of prolapse of the mitral leaflet due to chorda tendinea rupture), 23% of patients who presented with a left ventricular ejection fraction of 45–60% rarely exhibited overt symptoms but had higher mortality than patients with a left ventricular ejection fraction of >60%^58^. A left ventricular ejection fraction of <60% was associated with an adjusted hazard ratio for mortality of 1.51 (95% CI 1.22–1.87) and a left ventricular ejection fraction of <45% was associated with an adjusted hazard ratio of 2.46 (95% CI 1.67–3.61). The survival benefit of surgery was significant in groups with a left ventricular ejection fraction of <45% (adjusted HR 0.28, 95% CI 0.17–0.56) and in groups with left ventricular ejection fraction of 45–60% (adjusted HR 0.34, 95% CI 0.21–0.64)^58^. In addition, a left ventricular end-systolic diameter of ≥40 mm (a marker of left ventricular systolic function) is associated with an increased risk of mortality in patients with severe degenerative mitral regurgitation due to flail leaflets^59^.
Left ventricular global longitudinal strain (a measure of myocardial shortening during systole) might be a more sensitive and accurate measurement of left ventricular function than left ventricular ejection fraction. Left ventricular global longitudinal strain can be measured on echocardiographic and CMR images using specific software that quantifies myocardial fibre shortening. In a study in 593 patients with severe degenerative mitral regurgitation who underwent mitral valve surgery, a left ventricular global longitudinal strain of <20.6% (that is, more impaired myocardial function) was associated with significantly worse survival than a left ventricular global longitudinal strain of ≥20.6%. In addition, left ventricular global longitudinal strain had incremental prognostic value over clinical risk factors for long-term survival^60^. The role of left ventricular global longitudinal strain in determining the timing of surgery has not been explored. Impairment of left ventricular global longitudinal strain occurs earlier than the decline in left ventricular ejection fraction, which could be related to the structural changes that occur in the myocardium, such as reactive fibrosis and replacement interstitial fibrosis. These changes can be identified with gadolinium-based CMR imaging (gadolinium is a contrast medium that diffuses in the extracellular matrix). There is evidence that patients with degenerative mitral regurgitation present more frequently with mid-wall or patchy myocardial replacement fibrosis than patients with primary mitral regurgitation of other aetiologies^43^. In addition, reactive fibrosis which can be estimated with calculation of the extracellular volume with CMR imaging has been associated with the severity of regurgitation and is associated with the presence of symptoms, the need for mitral surgery and cardiovascular death^44^.
The onset of symptoms in patients with severe degenerative mitral regurgitation, regardless of left ventricular function, is also associated with poor outcomes^61,62^. Although ‘watchful waiting’ has traditionally been the treatment strategy in asymptomatic patients with severe degenerative mitral regurgitation^2,3^, there is growing evidence that patients with no or minimal symptoms have lower operative mortality and improved long-term outcomes if surgery is performed before symptom onset^63^. Indeed, propensity score matching of the early surgery group and the initial medical management group in the Mitral Regurgitation International Database (MIDA) registry confirmed higher survival after early surgery (HR 0.52, 95% CI 0.35–0.79; P = 0.002)^64^. Moreover, 10-year survival was improved with early surgery in asymptomatic patients (84%, 95% CI 78–90%) compared with initial medical management (78%, 95% CI 72–85%; P = 0.04). Early surgery also had an independent protective effect on risk of late heart failure. Notably in this study, 93% of patients received mitral valve repair, and mitral valve replacement was performed in only 7% of patients.
Several other clinical parameters are associated with poor outcomes in patients with degenerative mitral regurgitation. For example, a pulmonary artery pressure of >50 mmHg is a strong predictor of death (adjusted HR 2.03, 95% CI 1.30–3.18; P = 0.002), cardiovascular death (adjusted HR 2.21, 95% CI 1.30–3.76; P = 0.003) and heart failure (adjusted HR 1.70, 1.10–2.62; P = 0.018)^65^. Numerous studies have found an association between left atrial size and clinical outcomes using both linear dimensions (>55 mm) and a two-dimensional assessment of left atrial volume (>60 ml/m^2^)^66,67^. Paroxysmal and persistent atrial fibrillation is also associated with excess mortality, which persists even after surgical correction^68^. Other investigators have suggested that paroxysmal atrial fibrillation even in patients with moderate degenerative mitral regurgitation is associated with an increased risk of cardiac death and hospitalization owing to heart failure^69^.
Exercise stress testing can identify asymptomatic patients with degenerative mitral regurgitation who have a high risk of adverse outcomes. In a study in 196 patients undergoing exercise echocardiography with moderate to severe degenerative mitral regurgitation, exercise tricuspid annular plane systolic excursion (a measure of right ventricular systolic function) was associated with valve surgery-free survival, independent of resting left ventricular global longitudinal strain, exercise systolic pulmonary arterial pressure and resting right ventricular longitudinal strain (a measure of right ventricular myocardial shortening)^70^.
A MIDA score has been proposed in which clinical parameters are used to assess mortality risk, which might be useful in guiding decision-making^71^. The seven clinical parameters of the MIDA score and their point assignments (determined by Cox proportional hazards, competing risk and competing risk with imputation models) are age ≥65 years (3 points), presence of symptoms (3 points), right ventricular systolic pressure >50 mm Hg (2 points), atrial fibrillation (1 point), left atrial diameter ≥55 mm (1 point), left ventricular end-systolic diameter ≥40 mm (1 point) and left ventricular ejection fraction ≤60% (1 point). Survival rates at 5 years of patients with scores 0, 7–8 and 11–12 were 98 ± 1%, 57 ± 4% and 21 ± 10% with medical management, and 99 ± 1%, 82 ± 2% and 57 ± 9% after surgery, respectively. Although a simple risk score for both medical and surgical treatment (and which outperforms the standard surgical risk scores) would be of clinical use, the importance of integrating these scores with other comorbidities cannot be overemphasized.
Another phenomenon associated with degenerative mitral regurgitation is mitral annular disjunction^36^ (Fig. 4). Mitral annular disjunction has gained attention in recent years with the association of this finding with frequent premature ventricular beats and non-sustained ventricular tachycardia. CMR imaging has provided evidence of myocardial fibrosis and late gadolinium enhancement in patients with arrhythmias and mitral annular disjunction^37,38^. In early studies, mitral valve prolapse was consistently seen in patients with mitral annular disjunction; however, more recent studies have suggested that mitral annular disjunction associated with arrhythmias can occur without mitral regurgitation, and might be a separate morphological entity^37,38^.
Treatment of degenerative mitral regurgitation is mainly focused on interventional correction of the defect causing the coaptation failure through surgical or transcatheter valve repair (most commonly transcatheter edge-to-edge repair (TEER)). Surgical repair is more commonly used, and transcatheter repair is used in patients at high risk or in those with contraindications to surgery. With the exception of treatment for hypertension, medical management is mostly reserved for treatment of symptoms of left ventricular systolic dysfunction until mitral valve intervention is performed or in patients who are not candidates for intervention because of comorbid conditions.
The American College of Cardiology/American Heart Association guidelines have proposed clinical stages of primary mitral regurgitation on which to base clinical decision-making^2^ (Box 1). By contrast, the European Society of Cardiology guidelines provide recommendations for the treatment of severe degenerative mitral regurgitation and do not differentiate between the stages of disease proposed in the US guidelines^3^.
Mitral valve intervention (repair whenever possible) is generally recommended in patients with symptomatic severe mitral regurgitation or asymptomatic severe mitral regurgitation and signs of left ventricular dysfunction and dilatation^2,3^. However, studies have shown that survival after mitral valve surgery is reduced in those with stage C2 or D disease, as discussed above (in section ‘Prognosis and mortality’)^58,59^. Accordingly, several studies have evaluated mitral valve surgery in patients with asymptomatic severe mitral regurgitation and no signs of left ventricular dysfunction and dilatation (stage C1) to identify thresholds for intervention before the onset of irreversible left ventricular damage and a reduction in long-term survival rates following repair. Several clinical and/or imaging findings in these studies were independent predictors of decreased long-term survival in patients with stage C1 disease, including atrial fibrillation^68^, pulmonary hypertension^65^ and left atrial dilatation^67^. In addition, patients with degenerative mitral regurgitation and mitral annulus disjunction have increased risk of ventricular arrhythmias, particularly those with late systolic curling of the posterior mitral leaflet (exaggerated apical systolic motion of the posterior mitral annulus and inward excursion of the adjacent posterobasal myocardium that leads to papillary muscle traction and displacement of the posterior leaflet into the left atrium)^72^.
Based on these findings, the 2021 European and US valvular heart disease guidelines have given mitral valve surgery a class I recommendation (that is, therapy is recommended) in patients with severe degenerative mitral regurgitation and symptoms, and in asymptomatic patients with a left ventricular end-systolic diameter of >40 mm or a left ventricular ejection fraction of ≤60%^2,3^. Class II recommendations (comprising IIa (therapy should be considered) and IIb (therapy may be considered)) are given for patients with asymptomatic severe degenerative mitral regurgitation and atrial fibrillation, pulmonary hypertension or left atrial dilatation^2,3^. A class IIa recommendation is also given for asymptomatic patients with severe degenerative mitral regurgitation who are at low surgical risk, have a high likelihood of successful mitral valve repair (such as those with isolated prolapse of the central segment of the posterior mitral leaflet), and undergo surgery at a specialized heart valve centre. Finally, transcatheter mitral valve repair is given a IIa recommendation in the US guidelines and a IIb recommendation in the European guidelines for patients with severely symptomatic degenerative mitral regurgitation who are at high or prohibitive surgical risk^2,3^. Figure 5 summarizes the current treatment of patients with chronic severe degenerative mitral regurgitation.
Of note, no recommended medical or interventional treatment is available for patients with moderate degenerative mitral regurgitation, even though it is associated with excess mortality^57^. Serious complications such as malignant ventricular arrythmias and sudden cardiac death occur annually in 0.4–1.9% of patients with mitral valve prolapse, and these complications can occur in patients with stage B disease^38,73^. These complications have been thought to be due to left ventricular fibrosis in patients with arrhythmic mitral valve prolapse^74^, as regional left ventricular fibrosis is observed in degenerative mitral regurgitation, and ventricular arrythmias occur in patients with left ventricular fibrosis but without substantial mitral regurgitation^42,75^. Patients with degenerative mitral regurgitation and a history of sudden cardiac death or ventricular arrythmias are usually started on β-blocker therapy, although data from a small patient series suggest that transcatheter left ventricular ablation and even surgery (mitral valve repair combined with ventricular cryoablation) can be successfully undertaken in selected patients at high risk^36^. Future medical management of patients with moderate or less severe degenerative mitral regurgitation may involve targeted medications that address the underlying pathomechanisms leading to degenerative mitral regurgitation or antifibrotic medications to prevent the potential life-threatening complications of degenerative mitral regurgitation^9^.
The most common treatment of degenerative mitral regurgitation is surgical mitral valve repair. However, surgical mitral valve repair is greatly underused and is performed in only 29% of patients with severe degenerative mitral regurgitation^76^. The reasons for this underuse are unclear, but invasiveness and risks of surgery, which may be lower than perceived by the patient, undoubtedly have a role.
The primary objective of surgery inpatients with degenerative mitral regurgitation is to perform a durable and safe mitral valve repair. Mitral valve repair is superior to mitral valve replacement with regard to several important clinical outcomes including decreased risk of valve-related complications (infective endocarditis, thromboembolism and bleeding), and improved short-term and long-term survival^64,77^. Despite these clear advantages, mitral valve repair is performed in only 80% of patients undergoing surgery for degenerative mitral regurgitation, with some surgeons and some centres having lower repair rates^78^.
The main principles of mitral valve repair are mitral annuloplasty, optimization of leaflet coaptation and reduction of subvalvular forces^79^. There has been a gradual trend towards non-resectional (‘respect’) techniques to correct mitral valve prolapse over the past decade, mostly using polytetrafluoroethylene neochord sutures (see Supplementary Video 1), preserving the anatomy of the native mitral valve^80^. In addition, in many centres these operations are now performed via a less-invasive minithoracotomy or robot-assisted approach rather than through a median sternotomy^81^.
Surgical mitral valve repair is an invasive, but very effective, therapy for degenerative mitral regurgitation. Series from large-volume centres have demonstrated rates for freedom from moderate or severe recurrent mitral regurgitation of >90% and for freedom from mitral valve reoperation of >95%^80,82–84^.
As previously mentioned, early mitral valve repair is associated with a decreased incidence of heart failure and improved long-term survival compared with conservative watchful waiting in patients with asymptomatic (stage C1 and C2) degenerative mitral regurgitation^63,85^. However, serious complications can infrequently occur during mitral valve repair. In one study in 36,948 patients undergoing mitral valve surgery (83% mitral valve repair) for degenerative mitral regurgitation in the USA between 2011 and 2016, risks of major complications were 1.1% for stroke, 1.2% for renal failure, 0.1% for deep sternal infection and 1.2% for mortality^86^.
TEER was introduced as a treatment option for degenerative mitral regurgitation in 2003. TEER consists of fixing the prolapsing or flail segment to the contralateral (usually non-prolapsing) segment on the opposing leaflet with a transseptal positioned clip (Fig. 6). A flail width of <15 mm and a gap of <10 mm are echocardiographic predictors of TEER success in patients with degenerative mitral regurgitation^87^. TEER is associated with improved survival compared with watchful waiting (49% versus 37% at 4 years, P < 0.0001) in patients >65 years of age with symptomatic (stage D) degenerative mitral regurgitation^88^.
TEER is a less invasive therapy than mitral valve surgery and allows patients to mobilize and return to normal activities after the procedure earlier than after surgery. However, randomized controlled trials comparing TEER and mitral valve surgery are generally lacking. One trial (EVEREST II) randomized 279 patients with severe degenerative mitral regurgitation in a 1 manner to TEER or mitral valve surgery, and found improved safety, but decreased efficacy, in patients who received TEER compared with those who received surgery^89,90^.
Most TEER procedures are performed for secondary (functional) mitral regurgitation^91^, and data on the use of this procedure for degenerative mitral regurgitation (particularly long-term) are therefore limited. In the recently reported CLASP IID trial, at 6 months, 2% of patients showed recurrent moderate and severe mitral regurgitation and 1% of patients with degenerative mitral regurgitation needed mitral valve reintervention after TEER^92^. If surgery is required after TEER, most patients undergo mitral valve replacement rather than repair^93^.
Several technological advances in TEER have occurred in the past few years, and this treatment is being used in a rapidly growing number of patients including younger patients and those patients at lower risk^91^. Contemporary comparisons with surgical mitral valve repair are therefore urgently needed. Long-term follow-up is required in these comparative trials to adequately assess the compromise between the reduced invasiveness of transcatheter techniques and the increased effectiveness of surgical repair in patients who are not at high risk. Three ongoing randomized clinical trials are comparing TEER with conventional surgical mitral valve repair for degenerative mitral regurgitation in patients at high risk (NCT03271762), in patients at intermediate risk (NCT04198870), and in patients >65 years of age in any risk category (NCT05051033). In addition to these important clinical trials, more bench and preclinical studies are required to assess the long-term biomechanical effects of these two treatment strategies^9^.
Other transcatheter treatment options for degenerative mitral regurgitation have been used only in small numbers of patients. Transapical placement of polytetrafluoroethylene neochords on prolapsing mitral valve leaflets through a minithoracotomy has been performed, but recurrent mitral regurgitation remains a significant problem after this procedure^94^ (Fig. 6). First-in-human transseptal insertion of polytetrafluoroethylene chords on the prolapsing mitral valve with anchors to the papillary muscle has recently been described^95^. In addition, case reports exist of combined transcatheter mitral annuloplasty and transapical neochord placement, which mimic open surgical mitral valve repair^96^. Transcatheter mitral valve replacement is not normally performed in patients with degenerative mitral regurgitation.
Medical management of degenerative mitral regurgitation primarily consists of symptom control in patients with stage D disease with guideline-directed medical therapy of systolic dysfunction and heart failure, when present^2,3^. Vasodilator therapy can be used in patients with hypertension but should not be used in patients with normal blood pressure who have normal systolic function, as it may delay the symptoms. In patients with symptomatic acute degenerative mitral regurgitation due to new flail leaflet, nitrates and diuretics reduce filling pressures, and sodium nitroprusside can be used in patients with severe symptoms until mitral valve intervention can be performed. Patients with overt heart failure or systolic dysfunction due to long-standing degenerative mitral regurgitation should receive guideline-directed medical therapy, as in any patient with these conditions^97^.
Quality of life is an important metric to ensure appropriate patient care and to identify the patients who remain at high risk of cardiovascular events. No specific questionnaire is available that can guide the management of degenerative mitral regurgitation. The most frequent, subjective evaluation is the presence of dyspnoea complaints and classification according to New York Heart Association functional class^2,3^. However, these measures are not specific for degenerative mitral regurgitation. Some data are available on the effects of treatments for degenerative mitral regurgitation on the physical functioning of patients. One study used the 36-item Short Form Health Survey (SF-36) version 2 physical functioning scale to evaluate function at baseline and at 12 months after surgery in 330 patients with severe degenerative mitral regurgitation randomized to mitral valve repair performed with minimally invasive thoracoscopically guided right minithoracotomy or to conventional median sternotomy^98^. In this study, no differences were found in physical function score at 12 months (mean improvement 15.0 versus 14.1 points on a scale of 0–100). Moreover, no differences were found in terms of success of the valve repair or complications, and therefore these results highlight that the skills and success of the mitral valve surgeon are the most important factors for patients to consider when deciding to undergo mitral valve repair. Regardless of the surgical approach used, ensuring durable and effective mitral valve repair is the most important factor to achieve improved clinical outcomes.
With regard to TEER, the CLASP IID (Edwards PASCAL Transcatheter Valve Repair System Pivotal Clinical trial) randomized trial demonstrated that among patients with severe degenerative mitral regurgitation and prohibitive surgical risk, both available TEER systems similarly improved the score on the Kansas City Cardiomyopathy Questionnaire and the EuroQoL 5 Dimension 5 Level outcomes at 6 months follow-up^92^. These questionnaires are not specific to degenerative mitral regurgitation but may help in shared decision-making between patients and treating physicians. These questionnaires may help patients understand the limited functional capacity partially or totally related to the severity of degenerative mitral regurgitation and how an effective surgical or transcatheter intervention may help improve the clinical condition.
The overall burden of degenerative mitral regurgitation in terms of the number of disability-adjusted life years, deaths and prevalence is increasing globally, and therefore degenerative mitral regurgitation is a major threat to public health^7^. Improving access to diagnostic imaging, surgery and transcatheter interventions is key to improving the outcomes in patients with degenerative mitral regurgitation. Artificial intelligence-guided electrocardiography and echocardiography may help facilitate access to these diagnostic techniques and allow general practitioners to more accurately diagnose patients with degenerative mitral regurgitation who are currently not diagnosed by physical examination only^99–101^.
In addition, understanding the pathophysiological mechanisms that lead to each form of degenerative mitral regurgitation is important to implement preventive strategies or medical therapies that may halt the progression of the disease. Further research efforts should focus on genetic predisposition and proteomics signatures that may increase the risk of developing degenerative mitral regurgitation^9^.
Similarly, identifying patients with degenerative mitral regurgitation who are at risk of sudden cardiac death or malignant arrhythmias even in the absence of significant mitral regurgitation is a research priority. Ongoing randomized trials will better define the role of transcatheter therapies for degenerative mitral regurgitation. Of note, the Sustainable Development Goal 3 of the World Health Organization includes a 30% reduction in premature mortality from non-communicable diseases through prevention and treatment by 2030; degenerative mitral regurgitation is one of the important non-communicable diseases, and improvements in early diagnosis and treatment could contribute to this goal.