Floppy Mitral Valve/Mitral Valve Prolapse and Manifestations Not Related to Mitral Regurgitation: Time to Search the Dark Side of the Moon

Floppy mitral valve/mitral valve prolapse (FMV/MVP) represents a final common pathway for a wide variety of genetic/molecular and epigenetic factors resulting in the expression of this disorder. Several clinical manifestations of this complex entity are not directly related to the severity of mitral regurgitation (MR). Thus, clinicians and investigators who attempted to explain the symptoms of this disease solely on the severity of MR have missed the complete story [1‒3]. Further, MVP is a non-specific finding, while FMV is the central issue in the MVP story [1, 2, 4, 5]. The purpose of this review was to emphasize systemic manifestations of FMV/MVP not directly related to MR that constitutes a major part of its phenotypic expression and to outline pathophysiologic mechanisms contributing to these manifestations.

MVP results from the systolic movement of portion(s) of the mitral leaflet(s) extending above the atrioventricular junction into the left atrium (LA) during left ventricular (LV) systole. MVP can exist with or without MR. It is important to mention that prolapse of the mitral valve may be a non-specific finding that can result from several other mechanisms and not due to an abnormal mitral valve per se. For example, papillary muscle dysfunction or displacement due to myocardial infarction/ischemia and/or primary myocardial disease can produce MVP [1, 2, 5]. In addition, heart rate, intravascular volume, LV volume, arterial pressure, and myocardial contractility, among others can affect the mitral valve apparatus resulting in MVP even in a normal heart [1, 2].

It is well appreciated today that primary MVP is due to the pathological entity described as FMV, a term that comes from surgical and pathologic studies referring to the abnormal expansion of the area of the mitral leaflets with elongated or ruptured chordae tendineae (CT) and various degrees of mitral annular dilatation (Fig. 1). FMV is essentially the result of a weak cusp fibrosa allowing stretching and expansion to occur. These gross pathologic changes of the mitral valve occur secondary to histological alterations related to myxomatous and mucopolysaccharide infiltration, collagen dissolution, and elastin disruption and fragmentation [2, 4, 5]. Therefore, the attention should be focused on the FMV and not only on MVP. The great cardiovascular pathologists of the last century, Michael J. Davies and Anton E. Becker stated. “In our experience, primary prolapse is always associated with the morphological entity we will describe as the floppy valve. In other words, from our morphological stance, we can state that we have never seen a case of prolapse of unknown origin, at autopsy or following surgical resection, in which the valve leaflets were normal” [5]. Thus, instead of asking whether this patient has MVP, the question should be whether this patient has FMV.

FMV/MVP is a common disorder of the mitral valve apparatus with a broad spectrum of abnormalities from mild to severe (Fig. 1). Varying degrees of mitral leaflet thickening can be seen. A mitral valve with diffuse thickening is usually referred to as Barlow’s valve, whereas regional thickening of the mitral valve often associated with thin elongated CT is referred to as a fibroelastic deficiency valve [1, 2]. However, a continuum exists between these two entities, and thus, using the term diffuse or regional thickening may be more appropriate. Some variation exists between these two entities in gene expression, although overlap does exist [2].

Patients with FMV/MVP may be symptomatic or asymptomatic. Symptoms in those patients may be directly related to the degree of MR and/or to pathophysiologic mechanisms related to dysfunction of the mitral valve apparatus but not directly to the degree of MR [1‒3] (Fig. 1).

Prolapse of the FMV into the LA during LV systole sets in motion a number of dynamic events (Fig. 2), as detailed below. These manifestations may produce symptoms that are not related to MR.

Prolapsing of the floppy mitral leaflet(s) into the LA during LV systole results in the development of a third chamber within the border of the mitral valve annulus and the prolapsing mitral leaflets (Fig. 2, 3) [1, 2, 7]. Thus, during LV systole a certain amount of blood occupies the third chamber. In severe prolapse, the amount of volume that is occupied in the third chamber may represent a large proportion of the total LV stroke volume resulting in a significant decrease in the effective stroke volume [7‒9]. The average volume within the third chamber has been reported to be 15.7 mL (range 11.3–20.6 mL) in patients with bileaflet prolapse and 3.3 mL (range 1.2–5.5 mL) in patients with single leaflet prolapse [9]. The degree of MVP increases in the upright posture, which may further contribute to a decrease in the effective stroke volume and forward cardiac output. Decreased cardiac output may contribute to fatigue and exercise intolerance in certain patients with FMV/MVP. Previous studies from Ohio State University (OSU) have shown the inability of patients with FMV/MVP with no or trivial MR to maintain a normal cardiac output during exercise in the upright posture [1, 2, 8] (Fig. 3). From a pathophysiologic point-of-view, the third chamber acts like a LV aneurysm, as the volume of blood occupying this space does not contribute to the effective stroke volume. In addition, blood from the third chamber flows into the LV during diastole contributing to the diastolic volume that may result in LV remodeling. Moreover, the decrease in forward stroke volume may result in an increase in heart rate and sympathetic nervous activity further contributing to LV remodeling [2, 7, 9]. When significant MR develops, the third chamber and the LA constitute a continuous cavity and the third chamber essentially disappears.

FMV prolapsing into the LA occupies portion of its cavity that depends on the severity of prolapse and leaflet size (Fig. 2). This “space occupying lesion” alters LA hemodynamics and provides stimulus for neurohumoral activation [1].

In normal subjects, the distance between the papillary muscle tips and the mitral annulus during LV systole remains relatively constant. In contrast, in patients with FMV/MVP, the leaflet(s) are displaced into the LA resulting in papillary muscle traction [2, 10] (Fig. 2). The greater the prolapse of the mitral leaflet(s), the greater the traction on the papillary muscle. Sanfilippo et al. [10], using two-dimensional echocardiography demonstrated that in normal subjects the distance from the mitral valve annulus to the tip of the papillary muscle did not change significantly throughout LV systole (average 0.8 mm), while in patients with FMV/MVP this distance decreased significantly (average 8.5 mm). The superior papillary muscle motion in each individual patient was directly related to the superior displacement of the mitral valve leaflets due to prolapse (r = 0.93). Due to this traction, myocardial fibrosis may develop in the papillary muscles and the surrounding myocardium contributing to the development of ventricular arrhythmias [1, 2, 11‒13].

Papillary muscle traction may result in stretch receptor activation of the papillary muscle and the LV wall resulting in cell membrane depolarization and ventricular ectopy. Studies have demonstrated the existence of stretch-activated membrane channels in ventricular myocardium [14, 15].

The papillary muscles play an important role in the structure, function and dysfunction of the mitral valve apparatus. Mitral valve repair, to a certain degree, depends on papillary muscle morphology, especially when an “accessory papillary muscle” is present (in our experience approximately 5% of patients).

It has been suggested that mitral annular disjunction (MAD) may result in myocardial stretch during LV systole near the mitral valve and papillary muscle tip; due to this stretch, myocardial fibrosis may develop at the basal posterior LV wall contributing to the development of ventricular arrhythmias [16‒22] (Fig. 2).

In 142 patients who had reconstructive mitral valve surgery for significant MR due to FMV/MVP at Thessaloniki Research Heart Institute, MAD as defined by transesophageal echocardiography and direct inspection in the operating room was found in 54 patients (38%). The frequency of MAD was similar in both genders [2]. MAD is independently associated with bileaflet MVP, mitral leaflet redundancy, and myxomatous changes of the mitral valve. MAD is also associated with a higher risk of ventricular arrhythmias that persists after mitral valve surgery, but the association after surgery is weaker [13, 16‒18, 20‒22].

Endocardial friction lesions resulting from friction between CT and LV myocardium have been reported in patients with FMV/MVP who have died suddenly. It is possible that these lesions may be partially responsible for the development of ventricular arrhythmias. Fibrin deposits have also been observed in the angle between the LA and posterior mitral leaflet. These deposits may result in micro-embolism to the coronary circulation with subsequent myocardial ischemia and ventricular arrhythmias [23].

Human cardiac valves have distinct innervations that consist of both primary sensory and autonomic components [24]. The presence of these distinct nerve terminals suggests a neural basis for interactions between the central nervous system and the mitral valve (Fig. 2). The subendocardial surface on the LA aspect of the middle portion of the mitral valve is rich in nerve endings including afferent nerves; mechanical stimuli in this area caused by abnormal coaptation from FMV/MVP can result in abnormal autonomic nerve feedback between the mitral valve and the central nervous system. This mitral valve-brain interaction can result in the development of arrhythmias and/or symptoms related to autonomic dysfunction in patients with FMV/MVP syndrome (see later) [1, 2, 25, 26].

Symptomatic patients with FMV/MVP studied at the Clinical Research Center at OSU had higher 24-h urinary epinephrine and norepinephrine excretion compared to normal controls [27] (Fig. 4). In addition, the frequency of premature ventricular contractions (PVC) detected by ambulatory monitoring paralleled urinary catecholamine excretion. When 24-h urine epinephrine and norepinephrine were measured for three consecutive days, there was no day-to-day variability in these values in patients with FMV/MVP. Plasma epinephrine and norepinephrine at rest were also higher in patients with FMV/MVP compared to control subjects. Plasma epinephrine and norepinephrine increased after treadmill exercise in FMV/MVP patients and controls and were not different between the two groups; however, plasma epinephrine plus norepinephrine was greater in patients with FMV/MVP whose number of PVCs with exercise increased more than 10 beats per minute compared with patients in whom the frequency of PVCs remained relatively unchanged [27]. Isoproterenol infusion was also performed resulting in higher catecholamine levels in patients with FMV/MVP compared to control subjects. In addition, heart rate during isoproterenol infusion (0.5, 1.0, and 2.0 μg/min) was significantly greater in patients with FMV/MVP compared to controls and was dose related, whereas the baseline heart rate was similar in the two groups [28] (Fig. 4). Patients with FMV/MVP had normal thyroid function tests, plasma cortisol levels, diurnal variation of plasma cortisol, and excretion of 24-h urinary 17-ketosteroids and 17-hydroxycorticosteroids. FMV/MVP patients also had a normal response to oral glucose, but the glucose and insulin levels were higher than control subjects [27]. Furthermore, serum potassium in patients with FMV/MVP was in the low normal range; this most likely is related to a high adrenergic tone in these patients. High adrenergic tone and low potassium levels may predispose to cardiac arrhythmias [27, 28].

Pasternac et al. [29] also demonstrated that patients with MVP had higher total plasma catecholamine and norepinephrine levels when compared with controls both in the supine and upright positions. Plasma catecholamine levels were measured in the same patients 6 years later and did not change.

Studies from OSU have shown that diastolic time has a nonlinear relationship with heart rate [30]. Thus, small changes in heart rate will result in significant changes in diastolic time. A decrease in diastolic time with isoproterenol infusion was significantly greater in patients with FMV/MVP compared to control subjects due to a greater increase in heart rate in this group. Under certain circumstances, these changes in diastolic time may be of clinical significance as the greatest proportion of coronary blood flow occurs in diastole and subendocardial blood flow is almost entirely diastolic, which under certain conditions may compromise myocardial perfusion [30].

Pasternac et al. [31] reported higher atrial natriuretic peptide levels in 44% of patients with MVP as compared to controls; an inverse relationship was found between blood volume and atrial natriuretic peptide levels. In addition, an inverse relationship was seen between plasma norepinephrine levels and plasma volume. Further, Gaffney et al. [32] demonstrated an inverse relationship between blood volume and total peripheral resistance in patients with MVP; those with the highest peripheral resistance had the lowest blood volume, and patients with the lowest peripheral resistance had the highest blood volume.

Research related to FMV/MVP has been conducted at OSU for more than half a century. Therefore, it is not surprising that several OSU studies are included in this review article; however, to support our hypotheses, studies from many other international authorities performing pioneering work on the topic have also been included.

FMV/MVP can be found in a heterogenous group of patients with variable phenotypic expressions. Below are phenotypes that can be seen in patients with FMV/MVP without clinically significant MR.

Several decades ago, it became apparent to our group at OSU that certain patients with FMV/MVP had symptoms could not be explained by the degree of MR alone. At that time, we classified these patients as having “FMV/MVP syndrome” [3]. There were 313 patients (mean age 30 years) with FMV/MVP syndrome. All patients had a mid-systolic click and/or late systolic murmur on auscultation and the presence of FMV/MVP was confirmed by echocardiography or cineangiography. All patients had trivial to mild MR with normal LV systolic function. Symptoms included chest pain, dyspnea, palpitations, fatigue, exercise intolerance, orthostatic phenomena, presyncope, or syncope [3]. A subset of 65 patients (randomly selected) within this group were studied and demonstrated high adrenergic tone and hyper-response to adrenergic stimulation [27, 28]. Several other investigators have also described similar observations in patients with MVP that are not related to the severity of MR [32‒34].

More recently in a study from our group, 98 patients with FMV/MVP were evaluated in which 42% were found to have symptoms consistent with FMV/MVP syndrome. The most common symptoms in these patients were chest pain, dyspnea, palpitations, fatigue, exercise intolerance, orthostatic phenomena (tachycardia/hypotension), presyncope, or syncope. These symptoms were more frequent in women compared to men. Symptoms in these patients were analyzed from the time of onset until reconstructive mitral valve surgery was performed. All patients at the time of surgery had significant MR and indications for surgical intervention were based on current clinical practice guidelines [2, 35]. The median age of symptom onset was 30 years (range 10–63 years) and the median duration from onset of symptoms to mitral valve surgery was 16 years (range 3–50 years). Thus, it is unlikely that symptoms due to FMV/MVP were related to the severity of MR. The diagnosis of FMV in our study was established with transesophageal two- and three-dimensional echocardiography, and it was confirmed with direct inspection of the mitral valve in the operating room in all patients from an experienced surgeon. In the overall cohort, 40 patients had diffuse thickening and 58 patients had regional thickening of the mitral leaflets. The incidence of symptoms related to FMV/MVP syndrome was greater in patients with diffuse compared to regional thickening of the mitral leaflets [2, 35]. Palpitations were persistent in most patients, whereas other symptoms such as chest pain, dyspnea and fatigue disappeared after surgery. Atrial fibrillation was not responsible for symptoms in patients with palpitations. Thus, it can be concluded that patients with FMV/MVP may have symptoms consistent with FMV/MVP syndrome for several years prior to the development of significant MR, and therefore, these symptoms cannot be attributed to MR per se.

Several mechanisms may explain symptoms in patients with FMV/MVP syndrome. These include the development of the third chamber that may result in a decrease in stroke volume, especially in the upright position [8, 9]; papillary muscle traction that may result in chest pain and activation of stretch receptors leading to membrane depolarization and ventricular arrhythmias [10, 14, 15]; mitral valve nerve ending stimulation that may cause abnormal autonomic feedback between the mitral valve and the central nervous system; and neurohumoral activation due to prolapsing of the FMV into the LA [24, 29]. Symptoms in women with FMV/MVP syndrome also may be related to β-adrenergic receptor polymorphisms that increase the sensitivity to adrenergic stimulation [35] (Fig. 2).

Reconstructive mitral valve surgery, as a general rule, eliminates the third chamber and MAD, decreases papillary muscle traction, and alters the heart-brain interaction, among others. However, at present there is no information to support or refute the notion that early surgery may benefit some of these patients. MR due to FMV/MVP is progressive and eventually certain patients (10% or less of the entire FMV/MVP population) will require surgery during their life span.

It is possible that symptoms described several decades ago in patients with an irritable heart, neurocirculatory asthenia, or soldier’s heart, among others, were related to FMV/MVP syndrome [36]. In these earlier studies, autonomic dysfunction, hyperadrenergic state, hyper-response to adrenergic stimulation, and metabolic abnormalities were considered as a possible explanation for these symptoms [1, 35, 36].

The incidence of cardiac arrhythmias associated with FMV/MVP without significant MR was reported to be greater compared to the general population [1, 2, 37, 38]; however, in most instances, the lack of control subjects in these studies makes the results difficult to interpret. During the last 2 decades of the 20th century, there were 1,856 symptomatic patients referred to the electrophysiology laboratory at OSU, of which 271 patients (14.6%) had FMV/MVP without significant MR. In the FMV/MVP cohort, one or more electrophysiologic abnormalities were found in 220 of the 271 patients. Assuming that the prevalence of FMV/MVP in the general population is approximately 2%–3%, the data suggest that the incidence of symptomatic arrhythmias in patients with FMV/MVP is greater compared to the general population [2, 37]. However, selection bias cannot be excluded in this study.

In 1986, our group from OSU reported at the American College of Cardiology annual scientific meeting 9 patients (7 female) with FMV/MVP who had cardiac arrest; ventricular fibrillation was documented in 8 patients in which resuscitation was successful in 7. Eight patients had a history of palpitations and ventricular arrhythmias, 3 patients had a history of syncope, and 1 patient was asymptomatic. Seven survivors were followed from 3 to 14 years and were treated with beta-blockade therapy; 6 of the 7 patients were still alive at the time of publication [39]. These data were collected prior to the introduction of implantable cardioverter defibrillators into clinical practice.

Since then, significant progress has been made on the topic of sudden cardiac death in this patient population. Patients with FMV/MVP without significant MR who died suddenly tend to be relatively young women with bileaflet prolapse and symptoms consistent with the FMV/MVP syndrome. Although most of the patients are symptomatic, these symptoms (with the exception of arrhythmic syncope) are common and non-specific [2, 37‒42]. Of interest, family history of sudden cardiac death has been reported in 15%–20% of these patients. These patients usually have a history of complex ventricular arrhythmias, repolarization abnormalities in the inferior leads of the electrocardiogram, and bi-leaflet prolapse with thickened mitral leaflets (i.e., FMV) [43‒46]. QT dispersion and late potentials also have been reported in some of these patients. PVCs usually arise from the LV outflow tract, papillary muscle region, or Purkinje fibers, and could be polymorphic. On Holter monitor or other long-term rhythm recorders complex ventricular arrhythmias, couplet PVCs, and non-sustained or sustained ventricular tachycardia have been reported prior to sudden cardiac death in patients with FMV/MVP [2, 43‒46]. In our experience, PVCs have been shown to increase in FMV/MVP patients during isometric exercise and during the recovery period following aerobic exercise [27]. Fibrosis in the papillary muscle and LV inferoposterior wall, as detected by late gadolinium-enhanced cardiovascular magnetic resonance imaging and/or histologically at autopsy, may contribute to ventricular arrhythmias. Diffuse myocardial fibrosis has also been reported [13, 37, 47‒49]. MAD that may be associated with myocardial fibrosis and ventricular arrhythmias is often present in these patients [13, 18, 21, 37, 38, 48]. High adrenergic tone and a tendency for hypokalemia (due to high adrenergic activity) may also play a role in the development of cardiac arrhythmias [7‒28, 50, 51] (Fig. 4).

Infective endocarditis is more common in individuals with FMV/MVP as compared to the general population [52]. The abnormal surface area of the mitral leaflets, and not the MR per se, is responsible for endocarditis (Fig. 1c and 5) [1, 2, 53]. Infective endocarditis is almost never seen in patients with secondary MR in which the mitral valve is normal, while it can be seen in patients with FMV/MVP without MR [1, 2, 52‒54].

Familial and non-familial FMV/MVP may be associated with relatively benign extracardiac structural manifestations or with a heritable connective tissue (HCT) disorder. Glesby and Pyeritz [55] studied patients with FMV/MVP who could not be precisely classified within a recognized HCT disorder syndrome but showed certain manifestations of the Marfan syndrome including long limbs, thoracic cage deformation, striae atrophicae in the skin, and/or mild dilatation of the aortic root. The authors concluded that the phenotype in certain patients with FMV/MVP constitutes a continuum from Marfan syndrome at one extreme to isolated FMV/MVP at the other end. The MASS phenotype was suggested as an acronym to emphasize the involvement of the mitral valve, aorta, skeleton, and skin. In another study, the incidence of MVP was reported to be higher in patients with skeletal thoracic abnormalities as compared to the general population [56]. Low body weight and hypomastia also have been reported in patients with MVP [57, 58].

Clinical manifestations of FMV/MVP that are not related to the severity of MR constitute a major part of the phenotypic expression of this complex entity; these manifestations have not been emphasized [59‒61]. A better understanding of the mechanisms including genetics and epigenetics related to the development and progression of FMV/MVP will help precisely define the underlying molecular and pathophysiology mechanisms responsible for these symptoms; this in turn will assist clinicians to optimize management in these patients. If mitral valve surgery, which can eliminate the third chamber and MAD, decrease papillary muscle traction, alter mitral valve-brain interaction, and improve outcomes in these patients remains to be defined. At the present time, clinicians should be aware that FMV/MVP is not an isolated mitral valve abnormality resulting only in MR, but rather a complex entity with global systemic manifestations.

The authors have no conflicts of interest to declare.

There is no funding source for this manuscript.

K.D.B. and H.B.: literature review, interpretation of data, writing first draft, and critical revisions; A.P., C.I., K.M., and F.T. literature review, interpretation of data, writing, and critical revisions. All authors reviewed and approved final manuscript.