Valvular disease is a frequent cardiac pathology leading to heart failure and, ultimately, death. Mitral regurgitation, defined as the inability of the two mitral leaflets to coapt, is a common valvular disease and a self sustained pathology. A better understanding of the mitral valve histological layers provides a better understanding of the leaflet and chordae changes in mitral valve prolapse.
Mitral valve prolapse may occur in myxomatous degenerative abnormalities, connective tissue disorders or in sporadic isolated cases. It is the most common mitral abnormality of non-ischemic cause leading to severe surgery-requiring mitral regurgitation. In addition to standard echocardiographic investigations, newly implemented three-dimensional techniques are being used and they permit a better visualisation, from the so-called ‘surgical view’, and an improved evaluation of the mitral valve.
Hypertrophic cardiomyopathy is the most frequent inherited myocardial disease caused by mutations in various genes encoding proteins of the cardiac sarcomere, leading to a marked left ventricular hypertrophy unexplained by other comorbidities. The pathological echocardiographic hallmarks of hypertrophic cardiomyopathy are left ventricular hypertrophy, left ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. The systolic anterior motion of the mitral valve contributes to the development of mitral regurgitation and further narrows the left ventricular outflow tract, leading to more severe symptomatology. Cardiac magnetic resonance imaging accurately measures the left ventricular mass, the degree of diastolic function and it may also be used to distinguish phenotypic variants.
The clinical outcome of patients with these pathologies is mostly determined by the selected option of treatment. The purpose of surgical correction regarding mitral valve involvement is to restore valvular competence. Surgery has proven to be the only useful treatment in preventing heart failure, improving symptomatology and reducing mortality. Our approach wishes to enhance the understanding of the mitral valve’s involvement in hypertrophic cardiomyopathy and mitral valve prolapse from genetic, haemodynamic and clinical perspectives, as well as to present novelties in the grand field of treatment. IntroductionMitral valve structure and haemodynamicsGenetic causesLeaflet elongation and thickeningDiagnosis 5.1 Mitral valve prolapse 5.2 Mitral valve in HCMTreatment6.1 Mitral Valve Prolapse Management6.2 Management of mitral valve in HCM6.3 Clinical outcome6.4 Future perspectives Conclusions1The prevalence of valvular heart disease was reported to be 2.5% in 2015, in the USA alone1, with no difference in frequency between genders.2 The prevalence rises with age, affecting mostly people older than 65 years of age. The most frequent entities are aortic stenosis and mitral regurgitation (MR).3Valvular disease is a frequent cardiac pathology worldwide, which ultimately may lead to heart failure. The incidence of valvular disease in industrialized countries is increasing, as a result of the increase in general life expectancy.1 Other complications include arrhythmias such as atrial fibrillation (AF), endocarditis and death.4 The causes that lead to MR are classified as ischemic (due to the coronary insufficiency) and nonischemic. MR can also be classified as functional, due to annular dilation (as seen in dilated cardiomyopathies) or organic, in pathologies that affect the intrinsic structure of the valve, as seen in mitral valve prolapse (MVP).1 MR may also arise due to a congenital or an acquired pathological state.5MR is defined as the inability of the two mitral leaflets to coapt, leading to a systolic retrograde blood flow, from the left ventricle (LV) to the left atrium, which will result in volume overload of the left heart chambers and dilation of the mitral annulus. As a self-sustained pathology, it usually aggravates over time, leading to left heart failure.5,6 However, concurrent with ventricular remodeling, mitral leaflets can become inadequately small (as seen in dilated cardiomyopathies) or suffer a process of elongation. In hypertrophic cardiomyopathy (HCM), the leaflet elongation exceeds the needs of the reduced volume of the LV, further aggravating the left ventricular outflow tract (LVOT) obstruction and can predispose to systolic anterior motion (SAM) of the MV.5,7 In MVP, the leaflets are long and exhibit structural fibroelastic abnormalities.5,8Until now, the mitral valve (MV) was considered a passive structure. It has recently been demonstrated that it can react to the morphological changes that involve the LV and that it may also alter its structure irrespective of the state of the nearby structures.1The surgical treatment has an important role in the natural history of the disease and it has been proven to be the only treatment that may efficiently prevent heart failure, improving symptoms and reducing mortality by 70%. The best results were seen in asymptomatic MR, which supports the importance of an early and accurate diagnosis.This review highlights the mechanisms, the diagnosis and the current and future management of patients with mitral regurgitation, in the context of mitral valve prolapse and/or hypertrophic cardiomyopathy.9 The anterior leaflet is relatively fixed and its insertion occupies 1/3 of the circumference of the annulus, while the posterior one occupies the rest of the 2/3 and is more flexible, being the most susceptible to prolapse.9,10 Each of the leaflets is divided by two notches in three parts, called scallops, three anterior  and three posterior . This division is more evident in the posterior leaflet, and is an important aspect in the diagnosis and surgical treatment of MVP.10,11 The two leaflets are attached by their bases to the mitral annulus, whereas the edge and midportion of the leaflets are attached to the papillary muscles by means of the chordae tendineae. This system maintains an unidirectional blood flow during diastole, from the atrium to the ventricle and closes completely, preventing retrograde flow from the ventricle to the atrium, during systole.1,5The mitral apparatus is composed of two leaflets, the anterior and the posterior one respectively, the mitral annulus, and the subvalvular complex, which is composed by the papillary muscles and the chordae tendineae. Each of these structures has an important role in maintaining the function of the valve.5,12, dense collagen fibers, fibroblasts and glycosaminoglycans that easily absorb water and disperse mechanical stress when the two leaflets coapt.5,13 The chordae tendineae are strong structures with viscoelastic properties, which are composed of a core of collagen and a sheet of elastin.5 Due to the presence of the atrial smooth muscle fibers both on the annulus and the basal portion of the leaflet, the annulus will contract during presystole, further helping coaptation of the leaflets. It has been shown that the contraction of the annulus can be activated through ventricular smooth muscle fibers as well, although in this case MR may occur.14Histologically, it has been shown that the leaflets comprise, from the annulus to the edge, smooth muscle fibers, nerve fibersatrialis , spongiosa  and ventricularis .4,5 These components are modified in diseases such as MVP.15 On both sides, the leaflets are covered with a thin endothelial layer.4 Moreover, in the structure of the valve, there are valvular interstitial cells (VICs) that are connected through signaling pathways with the cells which compose the endothelial layers. When valve homeostasis is disrupted, myofibroblastic transition of the interstitial cells occurs, therefore promoting valve thickening.4,5,16In transverse sections, the valve is composed of three layers – 17,18The relative proportion of the valvular histological components varies with age, over time decreasing in cellularity and glycosaminoglycans, while increasing in fragmentation of the elastin network, collagen fibers and calcifications, thus promoting stiffness and loss of function of the valve.Mitral Valve Prolapse19MVP may occur in myxomatous degenerative abnormalities such as Barlow’s disease, connective tissue disorders such as Marfan’s Syndrome (MFS) and it may also be found in sporadic isolated cases.20-22 Autosomal dominant and X-linked forms have also been cited.19Through chromosomal mapping, it has been shown that myxomatous MVP has a genetic heterogeneity which implies mutations located on chromosomes 16, 11 and 13.23,24 Fibrillin-1 protein is the principal component of extracellular matrix (ECM) microfibrils and also one of the regulating factors of TGF-β activity, by inhibiting it.24 In patients with fibrillin deficiency, an enhanced activity of TGF-β was noticed. Also, in patients with TGF-β receptor 2 mutations, the altered receptor presented increased activity for its agonist.23,24Mutations of the fibrillin-1 (FBN1) gene which encodes the fibrillin-1 protein and mutations of the transforming growth factor β (TGF-β) receptor 2 gene are responsible for the occurrence of Marfan’s syndrome, as well as MVP.24It has also been shown that cells from valves with FBN1 mutations presented decreased apoptosis rates and increased cell proliferation.24,25 Filamin-A is an actin-binding protein, involved in maintaining membrane stability and sheltering cells against injury and also has the function to positively regulate the expression of TGF-β.24Another gene implicated in the etiopathogenesis of MVP is the Filamin A gene. An association between the up-regulation of Filamin A gene and X-linked forms of myxomatous valvulopathies has been shown.24An up-regulation of TGF-β – inducible gene H3, has also been found in myxomatous degenerated valves, which supports the theory that increased levels of this factor contribute to the cause of MVP. Moreover, high levels of TGF-β have also been found in the mitral valves of patients with isolated myxomatous MVP.26Another potential gene incriminated as one of the causes of MVP is the Dachsous Cadherin-Related 1 (DCHS1) gene. There is evidence that down-regulation of this gene determines abnormal valvular development, with structural valvular changes, as seen in MVP, with family aggregation and mostly involvement of the posterior leaflet.Hypertrophic Cardiomyopathy27 characterized by high grade left ventricular hypertrophy (LVH) which cannot be explained by other comorbidities (such as heightened afterload or restrictive diseases).28,29HCM is the most frequent inherited cardiomyopathy30, caused by mutations of the proteins that make up the sarcomere, in contrast to dilated cardiomiopathies, where mutations of cytoskeletal proteins are incriminated.HCM is an autosomal dominant disease30 The most frequently occurring mutations associated with HCM are found in cardiac myosin-binding protein C 3 (MYBPC3) gene, cardiac muscle β-myosin heavy chain 7 (MYH7) gene and troponin T protein type 2 (TNNT2) gene.30-32 Mutations of genes encoding cytoskeletal proteins may also be involved in the etiology of HCM.27 All of the above support the idea of a heterogenic etiology and phenotypic appearance of HCM.Until recently, it has been considered that mutations in 8 genes that codify the sarcomeric proteins are responsible for HCM, but it has been proven that up to 43 altered genes may modify the structure of myocites, further being involved in the etiology of this disease.30 It has been shown that some mutations predispose to an enhanced calcium sensitivity, which can lead to metabolic impairment and cytotoxicity.27 Heightened oxidative stress and altered expression levels of SERCA and phospholamban have also been cited in the pathology of HCM.33,34 Also it has been shown that mutations in the cardiac ryanodine receptor (mainly implicated in the genesis of arrhythmias) may be correlated with HCM, mostly with symmetric apical forms.30These mutations can interact at three main levels: sarcomeric function, metabolic pathways and calcium signaling pathways.27,30 Sporadic cases of HCM may also appear and are explained by a novel mutation or incomplete gene penetrance in the patient’s parents.30In up to 5% of cases HCM can be accompanied by skeletal muscle disorders, such as neuromuscular diseases.Mitral valve prolapse35,36 Both of these degenerative processes are associated with leaflet elongation and thickening, as well as chordal abnormalities.8,37MVP presents two main phenotypes that are recognized in the literature: myxomatous degeneration – Barlow’s disease and fibroelastic dysplasia.38 Members of the TGF-β family are implicated in mediating signals in the cardiac cushion. These reciprocal signals between the endocardial and myocardial cell layers promote the transformation of valvular endothelial cells (VECs) into (VICs).39 It has been shown, both on animal models40 and in human in vitro studies that TGF-β up-regulation plays an essential role in the pathogenesis of MVP. TGF-β activates VICs towards a myofibroblast-like phenotype and causes excessive remodeling of the ECM.41,42Heart valve development may help understand signaling pathways involved in MVP. Primordial valves derive from the cardiac cushions which are regional swellings of the ECM.38,43 VICs modify their phenotype to myofibroblast-like cells characterised by the expression of vimentin and α-smooth muscle actin and lack of expression of myosin heavy chain isoforms 1 or 2- markers of differentiated smooth muscle cells.44,45 Normal VICs are responsible for maintaining a tight balance between degradation and synthesis of the ECM proteins by means of enzymes such as matrix metalloproteinases (MMPs) - collagenase and gelatinases, as well as tissue inhibitors of MMPs.8,37 In contrast, modified VICs are responsible for an exceedingly high rate of collagen and elastin degradation compared to the production rate due to increased concentrations of various proteolytic enzymes.45-47 Furthermore, possible fibrocytes capable of differentiating into myofibroblasts that both produce and degrade collagen and elastin, may be present in myxomatous valves.38In myxomatous degeneration, the disruption of the ECM homeostasis is an essential mediator of the pathological changes.spongiosa.43,48 These muccoplysaccharides overflow onto ventricularis collagenous fibers and atrialis elastic fibers resulting in reduction of the collagen fibers and altered architecture of the leaflet. Nevertheless, there is an increase in type III collagen to the detriment of type I which is more resistant to traction.43,48 These changes promote valve thickening. The chordae undergo changes which reside in mucoid infiltration with glycosaminoglycans leading to the disrupture of their fibrous core.43,49 Grande-Allen et al. concluded that the predominant glycosamino-glycans in which the chordae are abundant are chondroitin/dermatan 6-sulfate, in contrast to leaflets which contained predominantly hyaluronan.49 These findings may account for both chordal and leaflet reduced tensile strength.50The excessive degradation of the ECM results in an extracellular accumulation of mucopolysaccharides which leads to the augmentation of the 51 The posterior superimposed fibrous tissue has been proven to be the main cause of posterior leaflet thickening rather than the expansion of the spongiosa. Furthermore, it is thought to be the result of the abnormal contact between leaflets and chordae.52There is evidence showing that non-ruptured choardae tendinae may be hidden (be covered up) by superimposed fibrous tissue of the leaflets, thus partaking to their thickening. Nevertheless, ruptured chordae may be partially included in the posterior superimposed fibrous tissue of the leaflets.36 Although the leaflets present as thin and smooth and the chordae slightly elongated, thickened lesions have been noticed in the leaflet segments exposed to MR.8,36 Thus, isolated regions of the leaflets are pathologically involved.35,36 This leads to the hypothesis that the thickened lesions are secondary to MR.8In fibroelastic dysplasia, there is a decrease in connective tissue which is deficient in collagen, elastin, and proteoglycans.Hypertrophic cardiomyopathyThere is an ongoing discussion regarding the pattern of geometrical changes of the MV in HCM.53 SAM is caused by elongation of the anterior and/or posterior leaflet(s) predominantly along with anterior displacement of the papillary muscles that, with each contraction, come in contact with the septum further aggravating LV obstruction and conferring undue mobility to the mitral apparatus.5 It has been shown that LVH is a contributing but not necessary factor for left ventricular outflow tract obstruction (LVOTO). While the exact cause of the increase in size of the mitral leaflets is unknown, Patel et al. has shown that patients with infraclinical or with very little LVH can present LVOTO strictly in a phenotypic variant of HCM that affects anterior mitral leaflet length, attachment of the chordae tendineae and bifid papillary muscle mobility.54His work is supported by older papers that suggest a hemodinamically independent cause of mitral valve remodeling.55-57Thickening and elongation of the mitral leaflets are often encountered in HCM patients. Historically, abnormalities in HCM were thought to be limited to SAM. Recently it has been shown that this anomaly is not unique to HCM.58,59This is in contrast to the belief that changes to the mitral apparatus are strictly a consequence of ventricular remodeling and ventricular mass.From this data Albert A. Hagège et al. has grouped the current available research into hypotheses.A. The Genetic Hypothesis60,61 The presence of an enlarged leaflet in patients with HCM without hypertrophy or LVOTO suggests that changes in the geometry of the valve are not due to leaflet stress or ventricular remodeling, but rather depends solely on a genetic defect (a sarcomere gene mutation).A posterior leaflet elongation of >14mm was observed in carriers of a morbid HCM mutation, but without hypertrophy or obstruction.62As mentioned above, MYBPC3 mutations are one of the causes of HCM. A study performed by Judge et al. shows that MYBPC3 knock-out mice with ecocardiographically diagnosed LVH have long and thick MV leaflets compared to controls. This abnormality occurs in the absence of LVOTO or SAM.B. The Adaptive Hypothesis58,59 A study performed on animals suggests that these changes might arise through reactivation of developmental embryonic pathways through endothelial-mesenchymal trans-differentiation (EMT). Cells synthesize α-smooth muscle actin in the atrial endothelium increasing collagen deposition. These changes are seen in the papillary muscles and chordae tendineae.63-65 As Hagège et al. concurs, this does not explain why leaflet enlargement occurs in the absence of SAM.This is the theory that postulates that mechanical stress applied to the leaflets causes leaflet lengthening.C. The Concurrent Disease Hypothesis:55The possibility of an independent MV disease that occurs with HCM has been brought up, namely the association between MVP and HCM. This theory has gained little traction due to the extensive studies and excellent diagnostic methods of MVP.D. The Developmental hypothesis63This hypothesis is developed from the feature of adult valves of being susceptible to embryonic signals that were active during fetal valvulogenesis. During myxomatous degeneration EMT is gradually reactivated. A surgical model shows similar changes occurring when MR is due to leaflet stretch.66 It has been proposed that periostin is the stimulus which dictates the differentiation of EPDCs. When a sarcomeric gene mutation is present, EPDCs that have differentiated into cardiomyocytes become fibroblasts under the stimulus of periostin.67An explanation of the wide variance of phenotypic appearances of HCM has been postulated. Epicardial-derived cells (EPDCs) are normally found on the surface of the heart. Physiologically they differentiate into fibroblasts as they migrate into the ventricular and atrial walls and into cardiomyocytes as they migrate into the interventricular septum.66 It directly affects restructuring of the ECM inducing remodeling and mediating response to tissue damage.68Periostin is normally found in tissues derived from the mesenchyme, most commonly in osteoblasts, periosteum and the periodontal ligament. It is also involved in cancer development and the mesenchymal development of the heart.69,70Several other animal studies have shown increased levels of periostin in HCM mice and it has been consequently postulated that it may be implicated in valvular degeneration.Figure 1).71New studies also suggest that in mice with HCM, genes that encode mutated contractile proteins cause EPDCs derived cardiomyocytes to become fibroblasts. This process occurs under an elevated level of periostin which may prove that periostin is responsible for collagen deposition on the MV, which may ultimately result in elongated leaflets  systolic atrial displacement of at least 2 mm over the long-axis annular plane, that can be accompanied or not by leaflet thickening.35,73,74 The disease is characterised by typical fibromyxomatous changes of the leaflet tissue and possibly chordal abnormalities such as lengthening.37,73 According to the Framingham Heart Study, MVP affects approximately one in 40 individuals, irrespective of sex and age.75MVP is the most common mitral abnormality of non-ischemic cause leading to severe surgery-requiring mitral regurgitation.35,36Barlow's disease and fibroelastic dysplasia are the two different pathologies most commonly associated with MVP. Early presentation with multiscallop prolapse, diffuse thickening of the leaflets, lengthened chordae and severe annular enlargement is characteristic of Barlow's disease. Fibroelastic dysplasia, unlike Barlow's disease, presents later in life, involves isolated regions of the valve, rarely produces severe annular enlargement and frequently associates rupture of chordae.75,76 The early misconception that this syndrome frequently occurs simultaneously with MVP was not confirmed by case-control studies.35,74There is no specific symptomatology that characterises MVP. However, a constellation of symptoms  and clinical findings  has been associated with this pathology under the name of MVP syndrome.35,72Symptoms occur when the compensatory ventricular dilation is overwhelmed and they indicate severe MR and LV dysfunction. Nonetheless, if the ventricular compensation of the severe MR is appropriate, the patient may remain asymptomatic for many years. Exertional dyspnea and exercise intolerance follow exhaustion of compensatory mechanisms and irreversible LV dysfunction occurs, as well as chordal rupture and sudden onset of AF.72 As far as the progression of the asymptomatic MVP to severe MR is concerned, there is evidence showing that 25% of the asymptomatic patients tend to develop a significant clinical form over the course of 3 to 16 years.77The importance of diagnosing MR as well as establishing its severity, lays in the excellent chance of improved quality adjusted life years for patients, provided they undergo intervention before symptomatology onset or irreversible ventricular damage.74MVP is more likely to be found in people having thoracic skeletal abnormalities and a leaner build.76,78When asymptomatic, this disease is usually discovered incidentally during clinical examination or during an echocardiogram.75,79 Classically, a dynamic, mid-to-late systolic click commonly associated with a late systolic murmur has been described.74 However, a late systolic murmur is more frequent than a mid-to-late systolic click.79MVP is usually suspected following auscultatory findings, physical examination being a diagnostic standard.74,80The click-dynamics may be perceived with specific maneuvers: an earlier click is produced by a reduced end-diastolic volume , whereas opposite maneuvers generate a click shift into late systole.35With chordal rupture and consequent leaflet flail, the murmur becomes holosystolic. A flailing posterior leaflet will generate a murmur radiating anteriorly which may mimic aortic stenosis.74,80 Thus, although a thorough physical examination is highly sensitive for echocardiographically documented MVP, its specificity is limited.80False positive auscultatory findings – non-prolapse related systolic clicks may occur. There are multiple causes for these findings such as bicuspid aortic stenosis, atrial myxoma and pericarditis. Nevertheless, echocardiographically documented prolapse may exist without auscultatory click or murmur.73,81 Cardiac ultrasound provides information regarding valve morphology, severity of regurgitation, global and regional ventricular function and allows correlations between valve structure, biomechanics and haemodynamics.5,73 The standard investigations for patient assessment with MVP are two-dimensional (2D) and Doppler echocardiography.82,83 Newly implemented techniques of three-dimensional (3D) echocardiography, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), permit visualisation of the MV from the so-called ‘surgical view’ thus enabling a better evaluation of the MV apparatus for pre-operative assessment.73,81The primary diagnosis mean of MVP is echocardiography.Transthoracic echocardiography5,73 Additionally, leaflet displacement in relation to each other  leads to malcoaptation, augmenting the severity of the regurgitation.5 Taking into account the saddle shape of the mitral annulus, distinct terms are used to describe leaflet displacement, while asserting prolapse magnitude.1,5,84 Thus, billowing refers to moderate degree prolapse when leaflet tips remain in the ventricle, , while leaflet flail denotes severe prolapse when leaflet tip coaptation fails and both bodies and tips are displaced into the atrium.1,5MVP is echocardiographically defined as valve leaflet displacement over the parasternal or apical long-axis annular plane during systole of more than 2 mm.5,72 Other anatomical abnormalities that should be evaluated are the LV dimensions and function by means of measuring the ejection fraction and end-systolic and end-diastolic diameters and volumes.72Valve characteristics that are evaluated by echocardiography in MVP are leaflet thickness and length, mitral annulus diameter and calcification, as well as the severity of MR.5,51 and it has been proven echocardiographically via parasternal long-axis view in diastole that mid-leaflet thickness is increased in 40% of patients with severe forms of this disease.5,85Generally, leaflets are elongated and thickened in MVP82,83 Doppler quantitative methods are more useful for grading the severity of MR1,83 compared with jet-based assessment which has major limitations. Proximal isovelocity surface area (PISA) method has become the standard quantitative assessment of MR.1,86 PISA allows measurement of effective regurgitant orifice area (EROA), regurgitant volume (RVol) and regurgitant fraction (RF).1,81,83 Regurgitation is considered severe in the setting of MVP when EROA is at least 40 mm2, RVol is at least 60 ml per beat and RF is at least 50%1,81 .As mentioned, leaflet malcoaptation leads to MR. Establishing the severity of MR is highly important, as an intervention could be considered even in asymptomatic patients with severe MR in the presence of LV dysfunction.1 Ventricular dysfunction is diagnosed in the setting of severe MR due to MVP when the ejection fraction is less than 60% and the end-systolic diameter is higher than 45 mm.83LV dimensions can also be performed by means of TTE. Volume overload is indicated by end-diastolic and end-systolic LV diameters and volumes, while ventricular function is assessed by end-systolic LV dimensions and LV ejection fraction.The role of transesophageal echocardiography35,81,87 It is preferred when TTE imaging is of poor quality or when complex, calcified or endocarditic lesions are being assessed.1 This investigation is mainly used on inpatients and during interventions to evaluate lesions and to monitor surgical results88 .MVP imaging obtained via TEE is of higher quality compared to TTE, as it provides better assessment of the etiology and quantification of the severity of MR.The emerging role of three-dimensional echocardiography1,812D echocardiographical evaluation is complemented and its results are enhanced by 3D echocardiography, as the latter allows assessment of structures that might be problematic when using 2D echocardiography, such as the mitral annulus.81,89 3D multiplanar reconstruction (MPR) is a revolutionary echocardiography technique with an improved accuracy of MVP description compared to 2D investigations and the benefit of combining these two methods (3DMPR and 2DTTE) as part of the pre-operative investigations is increased.11,893D TTE provides accurate data regarding anatomic localisation of prolapsing scallops, allowing better spatial localisation of commissures and quantification of MR severity.81,87,90 . It has been shown that 3DTEE is comparable to cardiac magnetic resonance (CMR) regarding feasibility and accuracy of diagnosis.81,913D TEE is superior to and has a distinct advantage over 2D TEE because imaging of the MV apparatus is more detailed and allows a more accurate localisation of prolapsing scallops11,81,83,893D echocardiographic assessment of patients with MVP is now recommended for routine examination and its potential benefit is highlighted by current guidelines and studies.The main application of CMR insofar as MVP is concerned, is strictly for pre-surgical patient assessment.92Assessment of MR requires quantification of: grade of MR in order to determine the need for surgical intervention, the mechanism through which MR has appeared , LV volumes for surgical risk assessment and myocardial viability in ischemic MR. the two investigations were almost equally effective in diagnosing prolapsed or flailing leaflets with TEE actually proving slightly more effective in this regard.93,94In two studies comparing TEE and CMR 94Although semi-invasive and operator dependent, TEE is excellent at accurately preparing patients for surgery and monitoring patient’s surgical response. CMR for MVP may be particularly useful in calculating LV dimensions in order to determine LV function and myocardial viability  - gradual accumulation of a gadolinium based contrast agent followed by its delayed wash-out). Cost-effective analyses for this matter have yet to be performed.95HCM is an inherited autosomal-dominant myocardial disease caused by mutations in various genes encoding proteins of the cardiac sarcomere, which is characterized by significant LVH unexplained by either chronic pressure overload or infiltrative diseases.96Due to an enhanced rate of recognition by means of echocardiography, as well as its autosomal dominant transmission, the prevalence of HCM in the general population is higher than it was previously estimated, with one in every 200 adults (0.5 percent).97 It has been shown that symptoms may be exacerbated by the decrease in cardiac preload due to splanchnic vasodilatation postprandially.98Symptoms can vary widely from individual to individual, comprising fatigue, dyspnea on exertion, anginal or atypical chest pain, palpitations and even syncope.99 The prevalence of AF in the setting of HCM increases with age.100Patients with HCM who associate diastolic dysfunction are at an increased risk for supraventricular and ventricular arrhythmias, notably AF and even sudden cardiac death (SCD), especially in athletes.97Patients with HCM may associate LVOTO caused by the hypertrophied IVS.101 Moreover, the SAM of the MV contributes to the development of MR and to the severity of the LVOTO, which represents a frequent cause of disabling symptoms in HCM.102Notably, the presence of LVOTO worsens the prognosis by deteriorating left ventricular performance and by favoring the progression to more severe symptoms as well as raising chances of heart failure and death.97In the setting of LVOTO, physical examination of the patient may typically reveal a suggestive systolic murmur. On auscultation, LVOTO can be emphasized by a harsh crescendo-decrescendo systolic murmur at the apex that may radiate to the axilla and base.54When these findings do not occur at rest, provocative maneuvers such as Valsalva maneuver or amyl nitrite inhalation reduce preload and may be used to augment the intensity of the murmur.103Conversely, inspiration or hand grip increase afterload and therefore diminish the intensity of the murmur. For this reason, dynamic auscultation is crucial for the diagnosis of HCM.1Physical signs of MR associated to HCM may include cardiomegaly and a laterally displaced apical impulse. It is essential to seek for a loud holosystolic murmur best heard at the apex which may radiate into the axilla.Electrocardiography97 Signs of LVH associated with atrial enlargement  due to persistent MR are highly suggestive for HCM. LVH results in increased precordial voltages and repolarization changes . In the apical form of HCM, “giant negative T waves” in precordial leads may be observed in leads V2-V4. The axis may be deviated leftward.1A routine electrocardiogram (ECG) is a sensitive yet not specific method to diagnose HCM.Deep, narrow Q waves in lateral  and inferior  leads indicate asymmetrical septal hypertrophy.1 Features of Wolff Parkinson White syndrome  are frequently associated with HCM.104Furthermore, dysrhythmias such as supraventricular tachycardia may occur and even trigger malignant arrhythmias, eventually leading to SCD. AF is commonly seen in patients with advanced MR.Further investigations using noninvasive cardiac imaging are required in order to establish the diagnosis of HCM and evaluate the severity of the pathological changes.100,105Performing an echocardiography on all patients suspected of HCM has the purpose of identifying the presence of cardiac morphology abnormalities such as LVH as well as appreciating the extent of systolic and diastolic dysfunction and diagnose the presence of MR.106Comprehensive TTE is the initial imaging technique which demonstrates the pathological hallmarks of HCM: LVH, LVOTO and SAM of the MV.Tranthoracic echocardiography972D echocardiography provides useful data concerning the distribution and extent of LVH, especially during diastole in parasternal short-axis plane. Alternative imaging windows are also used to confirm measurements.105The criterion of a wall thickness exceeding 13 mm is used to diagnose HCM.107,108 and usually the LV ejection fraction is preserved. Evidence suggests that wall hypocontractility may develop before hypertrophy becomes evident.109The most commonly identified phenotypic variant of HCM is asymmetric hypertrophy, preferably localized within the basal segment of the anterior septum. This type is associated with LVOTO in 20-30% of cases110SAM of the MV consists in the anteriorly deviated movement of the mitral leaflets towards the ventricular septum during systole.111 The resultant pressure gradient leads to SAM.In patients with HCM, flow through the narrowed LVOT is characterized by elevated velocities and reduced pressure of blood ejection (Venturi effect).1,102 As evidence shows, SAM has been observed independently from HCM112 and precedes the increase of LVOT flow gradients.113In addition, structural abnormalities appear to be responsible for SAM of the MV.114SAM may occur in a wide range of patterns, depending on whether one or both mitral leaflets are involved and the place of chordal attachment .102,115SAM of the MV may result in dynamic LVOTO due to the impingement of the MV leaflets upon the hypertrophied IVS. The severity of obstruction in the LVOT is highly influenced by SAM, as the longer the mitral leaflets are dragged anteriorly, the narrower the LVOT becomes and the flow velocity increases further.3. Increased velocities from the LVOT to the aortic valve plane due to SAM are marked by the turbulent appearance of the color Doppler flow115 .LV outflow gradients are measured using continuous-wave Doppler imaging primarily in the apical long-axis view97,106Provocation tests using amyl nitrite, exercise or the Valsalva maneuver may be applied either for an enhanced diagnosis or for evaluating the response to pharmacologic agents.106,110As leaflets are pulled into the LVOT during SAM of the MV, leaflet apposition becomes asymmetric and incomplete, resulting in a MR jet which is directed posteriorly.116 In terms of timing, LVOTO typically has a late systolic peak and a “dagger shaped” continuous-wave profile.When the LVOT jet is present concomitantly with a MR jet, distinguishing signals from the two is challenging and the efficacy of a single flow assessment may be altered106Conversely, MR ejection period lasts longer and usually reaches outstanding peak velocities of more than 6 m/s during mid-systole.117The MR jet flow is easier to differentiate from LVOT jet flow when the Doppler beam is progressively oriented from the LVOT flow towards the MR flow. Furthermore, the two flows can be displayed separately when sweeping constantly from one flow to another.118 For instance, when the posterior leaflet is not mobile or long enough to follow the anterior leaflet, malcoaptation occurs and an interleaflet gap results.102 Chordal and papillary muscle displacement also interferes with leaflet coaptation, as they impose the limits of mobility allowed.119Evidence shows that leaflet length and mobility are important determinants of the severity of MR.2D imaging gives information upon leaflet morphology and coaptation efficiency.106Continuous-wave Doppler evaluates velocities from the LV apex to the MV plane in an attempt to determine the peak flow of MR.100 Papillary muscle insertion abnormalities are easier to identify when using off-axis views with 2D echocardiography.106A comprehensive examination is done in both parasternal and apical views from the medial to the lateral margins of the MV.Transesopahgeal echocardiographyTEE studies are mostly used for thorough periprocedural evaluation for planning purposes, although they are also useful when transthoracic views are not accurate enough.102,120, TEE may also identify any additional concurrent organic cause of obstruction such as a subaortic membrane associated with dynamic obstruction.105While TTE shows elongated leaflets in patients coming to surgeryThree-dimensional echocardiography121 and thickening as a consequence of repetitive septal contact and hypertrophied, anteriorly displaced papillary muscles.1,117By means of real-time 3D echocardiography the following morphological changes were identified to be responsible for SAM: leaflet elongation122,123, degree of diastolic function  and possibly even the risk of SCD124) and it may also be used to distinguish between phenotypic variations of HCM .123 CMR may also be used for monitoring post-surgical and post-pharmacologic treatment responses.123-125.As mentioned above, diagnosis of HCM traditionally relies upon clinical assessment and TTE in order to identify LVH, SAM and LVOTO. Heterogeneous phenotypic expression of the disease and technical limitations of echocardiography further complicate the diagnosis. CMR is an effective non-invasive imaging technique that can accurately measure LV mass126.Particular cases of patients with non-diagnostic clinical and TTE investigations, but with positive HCM on CMR  have been reported107,124Insofar as technique is concerned, CMR benefits from the feature of various enhancement patterns in afflicted myocardium, namely LGE. The technique is based on gradual accumulation of a gadolinium based contrast agent followed by its delayed wash-out. LGE appears in a number of diseases that involve the myocardium, myocarditis, various cardiomyopathies and myocardial infarction being the most common ones.126,127Non-invasive injection of the contrast agent helps describe tissue characteristics and may identify interstitial and replacement fibrosis typical for HCM. .LV crypts. Asymptomatic HCM patients were found to have crypts of up to 12 mm in the postero-basal ventricular septum which was undergoing hypertrophy. The significance of LV crypts remains to be determined.64,65Perhaps the most recent and important of CMR’s uses is the early detection of negative phenotypes, so called pre-clinical HCM. CMR studies by Maron et. al and Germans et al. have shown structural changes in the LV wall, in the form of 128Asymptomatic patients with minimal disease need an initial risk stratification by means of echocardiographic evaluation. If clinically significant MR is absent and thin leaflets are observed, the patient is encouraged to pursue a normal lifestyle, with clinical examinations and echocardiographic evaluation at every 3-5 years.In symptomatic MR and/or left ventricular dysfunction associated to MVP, afterload-reducing agents  are used for maintaining cardiac output. Caffeine, alcohol and cigarettes should be avoided.128,129In AF, maintenance of a normal ventricular response is ensured by administering beta-blockers and calcium channel blockers. Anticoagulants, such as anti-vitamin K drugs, are also recommended especially in patients with risk factors but also for the ones post MV replacement surgery.83The use of prophylactic antibiotics prior to periodontal and surgical procedures, although highly recommended in the past, has been limited to selected cases in recent years, according to the American Heart Association (AHA) guidelines.129Inotropic agents should be used in chronic severely symptomatic MR.ESC/EACTS guidelines suggest diminishing filling pressures in acute MR (with or without hypotension) with nitrates and diuretics, as well as afterload and regurgitant fraction reduction by means of nitroprusside therapy or an intra-aortic balloon pump.82In the case of hemodynamic shock, inotropic agents and an intra-aortic balloon pump should be used.72. The purpose of surgical correction in MVP is to restore MV competence.Although pharmacological therapy might relieve symptoms in severe MR or LV dysfunction (ejection fraction <60% or end-systolic diameter >45 mm), it cannot alter the natural development of the disease, surgery remaining the ultimate treatmentMitral valve replacement130An option for surgical correction is MV replacement. It can be performed using either a mechanical, or a biologic prosthesis. Although this method is considered to have the highest long-term efficacy, it has several drawbacks. Mechanical valves pose a risk of thromboembolism, thus needing lifelong anticoagulation therapy, while bioprosthetic valves rapidly deteriorate. Additionally, there is a high susceptibility of prosthetic-valve endocarditis or chordal cleavage during surgery.Mitral valve plasty83,131 MVP is usually repaired, either by resecting the flail and prolapsing leaflet scallop or by reconstructive techniques with artificial polytetrafluoroethylene (PTFE) chords. Annular dilation is often associated with MR and is corrected with a complete or partial annuloplasty ring. Posterior leaflet prolapse is more common, leading to severe MR. However, it has a higher success rate of durable repair compared with anterior leaflet prolapse or severe bileaflet prolapse. Ultimately, the most important indicator of long-term life expectancy in mitral repair remains the expertise of the surgeon.Surgical repairs are the preferred treatment for MVP. Although being associated with a higher post-operative recurrence of MR , mitral plasties have a lower peri-operative mortality.72Despite median sternotomy being the standard surgical approach, minimally invasive techniques are increasingly used nowadays , while the robotic approach is also gaining popularity. Both methods include partial sternotomies and restricted or mini-right thoracotomies.Transcatheter mitral valve repair72,129A cutting-edge method in MVP treatment is the transcatheter MV repair. The technique that mimics the surgical procedure proposed by Alfieri et al. offers an alternative to surgery for patients with symptomatic severe MR and high surgical risk. MitraClip therapy consists in edge-to-edge leaflet repair by clipping together the free edges of leaflets at their mid-portion. The Endovascular Valve Edge-to-Edge Repair Study (EVEREST II) compared MitraClip to surgery, showing that percutaneous repair of the mitral valve was less effective in reducing MR. However, this type of transcatheter repair was associated with similar improvement in clinical outcomes and with superior safety.Papillary muscle shortening132 Papillary muscle repositioning was also proposed as a reliable and safe technique in the repair of anterior leaflet prolapse, with excellent clinical and echocardiographic long-term results.133Papillary muscle shortening is another technique for MVP treatment used in the cases of abnormal muscle anatomy. There are two approaches for this technique: one by cutting a muscle section. An alternative method involves placing and tying a suture through the top of each muscle end and then passing it through the base, shortening them.Replacement of chordae tendineae134 Options to manage elongated chordae in MVP include natural chordal transfers (rarely used nowadays) or PTFE neochord replacements.132 Potential advantages of the “non-resection” approach include: preserved leaflet mobility, larger coaptation surface, implantation of larger prosthetic annuloplasty ring, which provides lower gradients due to larger orifice area, and lack of changes in annular geometry.134While mitral scallop “resection” methods have provided excellent long-term results, there is increasing evidence that supports “non-resection” techniques, with a “respect rather than resect” philosophy.135 During the last 6 years, two transcatheter techniques of placing artificial chordae have been developed72 The correct length of the chordae is determined by real-time echocardiographic guidance while observing the improvement in MR .132,135However, some improvements have been brought to the PTFE chordal replacement technique, as the classic procedure involves open-heart surgery.105In asymptomatic patients, the main concern is instructing them regarding the management of their disease. Intense physical activities should be avoided, changing their lifestyle should also be encouraged. Treatment of risk factors is also of paramount importance. Pharmacological therapy is usually the first line of treatment in order to prevent complications and disease progression. On an empirical basis, beta blockers and calcium channel blockers are the elected medications. Invasive treatment techniques are not recommended for these patients.136In symptomatic patients, the main concerns are treating symptoms, improving functional capacity and postponing the invasive treatment techniques. Symptoms such as angina or dyspnea should be treated using beta-blockers. For patients who present side effects or contraindications to beta-blocking drugs, verapamil or diltiazem therapy is recommended. AF should be managed using anticoagulation with vitamin K antagonists or direct thrombin inhibitors and anti-arrhythmic such as amiodarone, disopyramide or sotalol.137-142Patients with progressive disease  and who are refractory to medical therapy are suitable candidates for the following: septal myectomy with or without MV repair, alcohol septal ablation, chordae resection, papillary muscles surgery or even heart transplant.Septal myectomy140 and improve the MR grade. A study showed that after septal myectomy, all of the patients experienced a significant reduction in MR degree: no MR in 80%, mild in 19%, moderate in 1%.142 The main complications were atrioventricular nodal block, ventricular septal defect and aortic regurgitation.137It is a surgical procedure aimed at reducing the muscle thickening by removing a small amount of the thickened septal wall to decrease LVOTO143, including a decrease in the LVOT gradient from 78 mmHg to 11 mmHg and an improvement in 98% of the patients concerning the NYHA class .144,145This method is now associated with a less than 1% mortality riskSeptal myectomy and mitral valve repair138Whereas the surgical septal myectomy is the gold standard procedure in treating HCM patients, it does not directly address the involvement of the MV in the pathophysiology of HCM. A two-step procedure seems more efficient: septal myectomy, followed by MV repair with reconstruction.138 Other studies also support the dual method, as the data suggests a more satisfactory outcome compared to myectomy alone.146 Another study has also shown a significant clinical improvement in patients that underwent septal myectomy combined with MV repair, rather than in patients that underwent septal myectomy alone.147Excellent improvements have been observed, regarding the haemodynamics of the MV and clinical symptoms: NYHA class III and IV patients reached NYHA class I; the control echocardiography showed no MR, with a mean resting gradient of 15 mmHg (from a prior 73.5 mmHg).Septal myectomy and chordae resection140Another surgical option could be septal myectomy combined with the resection of the MV anterior leaflet chordae. A long-term study analysed the efficiency of this technique . The results showed improvements regarding the NYHA class: from class III-IV to asymptomatic and class I-II post-surgery. Also the LVOT gradient changed from 82 to 9 mmHg and the MR changed from grade 3 and 4 to lower grades.Papillary muscles surgery102 The surgical reorientation is performed to prevent ischemia, by suturing the fibrous portion of the papillary muscle in order to realign them as necessary and to reduce the hypermobility. The mean perioperative (114 mmHg) and predischarge (16 mmHg) LVOT gradients, show the effectiveness of this method. Moreover, the results have been compared to those of the patients who underwent isolated myectomy and myectomy plus MV repair/replacement, outlining the similarities regarding the outcome and concluding the surgical alternative for those who do not meet the septal thickness criterion for myectomy.148Papillary muscle surgery is the surgical approach that should be considered regarding displacement of the base of the anterolateral papillary muscle or its abnormal muscular insertions into or near the A1 scallop. Studies have shown the possibility of a longitudinal excision to thin the abnormal papillary muscle which caused the obstruction.Alcohol septal ablation149 It is considered an alternative to septal myectomy when the latter is unsuitable. The reported survival rate at 5 years is 91.7%. However, the procedure should not be encouraged in patients with marked septal hypertrophy (>30 mm), who do not meet the age requirements (>21 years of age) and have concomitant heart diseases that need surgical correction . Another important aspect is the risk of developing post-procedural AF or atrioventricular block.139Alcohol septal ablation (ASA) is a percutaneous, minimally invasive procedure which induces localized myocardial infarction, resulting in the thinning of the IVS, therefore leading to the reduction in dynamic outflow obstruction. For this method to be applied, LVOT should have a gradient more than 50 mmHg.Pacing and Implantable cardioverter defibrillators (ICDs)105 Despite the low mortality rate, complications are common, therefore the benefits and risks of this therapy should be carefully weighted.150-153Permanent pacing and ICDs are suitable for patients who cannot undergo surgical treatment and are at risk of developing life-threatening arrhythmias.Heart transplant154 Nonetheless, their survival rates after this procedure are comparable to those of patients transplanted for other cardiovascular diseases: the survival rates at 1, 5 and 10 years were 85%, 75% and respectively 61%.141HCM patients represent a small subset (<1%) of the whole patients undergoing heart transplant.Mitral Valve ProlapseThe outcome of patients with MVP mainly depends on the chosen treatment.Surgical treatment comprises of either repairing or replacing the MV.155,156 while others show comparable results. Bio-prostheses are more prone to reoperation. Therefore, the type of prosthesis cannot accurately predict the outcome of MVP patients who underwent valvular surgical replacement.157In terms of replacement surgery, bio- and mechanical prostheses have similar mortality and follow-up rates. Bleeding risk evaluation offers varying results with some studies showing a more significant risk of bleeding for mechanical valves158MV repair carries a vastly lower mortality compared to replacement surgery both immediately following surgery and on long-term follow-up . This tendency is also valid for myxomatous valvulopathies that required surgical treatment, making valvular repair the elective treatment for patients with MVP.Hypertrophic cardiomyopathy159-162 Over 65 years of age, however, ASA had a more significant decrease in gradient and symptoms than septal myectomy. Regarding mortality, certain studies have shown similar peri-procedural rates162,163, while others have shown a higher incidence of complications in the case of ASA.164,165 There is an ongoing debate which procedure should be favored, this being highly dependent on patient types and operative expertise.166Patients under 65 years of age who underwent septal myectomy had better survival rates and lower severity of symptoms than patients who underwent ASA. ASA patients became completely asymptomatic in only about half of the cases.155A study compared LVOT gradient, MR and SAM in patients who underwent septal myectomy and concomitant MV repair or MV replacement. Preoperative peak LVOT gradient was 63.7 mmHg with severe MR present in 88% of the cases and with SAM in 94%. Following surgery LVOT gradient decreased to 10 mmHg, 21% of patients, still presented chordal SAM and MR was absent or mild in 75% of cases and moderate in 21%. At late follow-up, LVOT decreased to 2.5 mmHg, SAM was no longer present in any of the patients and only 2 had MR and 84% of patients were in NYHA class I or II.72Surgery is prone to remain the gold standard therapy in low-risk or intermediate-risk patients with MVP.72,135 Supporting this concept, robotic surgery has come to the aid of MVP treatment. This technique allows increased operative dexterity and ambidexterity, higher degree of movement freedom (compared with the endoscopic approach), tremor-free movements, by-pass of the fulcrum effect (often manifested during endoscopic procedures) and use of 3D high definition imaging. Furthermore, patients directly benefit from the smaller incisions, shorter length of hospitalisation, sooner return to the pre-operative level of functional activity and decreased blood transfusion requirements. Some limitations in robotic MV surgery remain the increased operative times and lack of haptic feedback. Morbidity and mortality rates are similar to both classic cardiac surgery and minimally invasive procedures.167The new trend nowadays is developing minimally invasive techniques.168Additionally, a novel patient-specific virtual valvular repair strategy was implemented, in order to decide pre-operative selection of the optimal repair techniques. Personalized computational modeling for MV repair, along with 3D echocardiographic guidance can provide higher outcome predictability and, ultimately, more effective medical care for the patient.169In the pursuit of overcoming some of the MV replacement limitations, tissue engineering-based techniques have been approached. Among various scaffolds used in tissue engineering, the decellularized heart valve (DHV) has attracted much attention, as a result of its native structure and comparable haemodynamic characteristics. The clinical application of DHV remains under debate .170 and the attainment of a controlled expression of exogenous genes.171 Systemic administration of cardiac adeno-associated virus (AAV) and a cardiomyocyte-specific promoter specifically targets the heart.The applicability of gene therapy is limited to dominant monogenic muscle disorders such as HCM, mitigating the consequences of myofilament mutations. Limitations comprise the receptivity of muscle to gene transduction, gene delivery using vectors such as adeno-associated virus 9 (AAV9)172In severe cases of inherited cardiomyopathy associating systolic heart failure with a heart transplant as an ultimate treatment option, gene therapy plays an important role. Commonly, homozygous and double heterozygous mutations in the sarcomeric genes predispose to rapidly progressive cardiomyopathies.-splicing, exon skipping and RNA silencing.173Gene therapy may either remove mRNA mutations or introduce functional proteins in the place of mutant endogenous ones. Techniques directly targeting endogenous mutant sarcomeric mRNA or RNA are spliceosome-mediated RNA trans-splicing (SMaRT) is an approach which creates a full-length repaired mRNA by splicing together a mutant pre-mRNA and a therapeutic pre-trans-splicing molecule, both transcripted independently (delivered by AAV).174Spliceosome-mediated RNA trans175 Despite the small internal deletion, the protein’s functionality is unaltered. AAV9 administration in myosin-binding protein C 3 – knock in mice (MYBPC3-KI mice) produced a stable functional protein which temporarily prevented the disease phenotype.176 However, reaching the appropriate level of intracellular oligonucleotide that entirely suppresses missense mutations remains a major challenge.171Different strategies use antisense oligonucleotides (AONs) to mediate the skipping of mutated exons. Their role is to restrict the binding of regulatory splicing proteins that mediate exons inclusion into the mature mRNA by concealing exonic splicing enhancer motifs.177Severe sarcomeric cardiomyopathies due to bi-allelic MYBPC3 mutations have been associated with fewer mutant proteins. The causal therapy in this particular case consists of replacing endogenous mutant myosin binding protein-C (cMyBP-C) with exogenous functional cMyBP-C. In a recent study performed on homozygous MYBPC3-KI mice, one systemic injection of AAV9 encoding cMyBP-C under the control of human cardiac troponin T promoter in neonatal mice has enabled a 34 week long prevention of the disease phenotype, namely LV hypertrophy.2+ desensitizers owing to their intrinsic Ca2+-binding properties. Signaling of muscle contraction is impeded by compounds that bind to either the N-terminal regulatory domain or the C-terminal structural domain of cTnC. Consequently, the Ca2+-dependent interaction between cTnC and cardiac troponin I (cTnI) is prevented. Furthermore, cTnC is structurally homologous with calmodulin (CaM), making CaM-binding compounds potential modulators of Ca2+ sensitivity in the cardiac myofilament.173Cardiac troponin C (cTnC) is the target of genetic manipulation with the aim to reverse primary functional changes of the sarcomeres. Newly formed cTnC mutants are produced in order to behave as Ca178Vertically transmitted HCM may be prevented when a couple undergoes assisted reproduction by in vitro fertilization. First,one cell is removed from each embryo and analysed for specific mutations. Subsequently, mutation free embryos are selected and transferred into the uterus.179Conclusively, based on the fact that HCM does not significantly affect longevity, genetic engineering is not a priority nowadays. Gene therapy is mostly suitable for recessively inherited defects induced by mutations which partially or completely alter enzyme function.The mitral valve undergoes similar leaflet elongation and thickening changes, although through different mechanisms, in mitral valve prolapse and in hypertrophic cardiomyopathy. These mechanisms involve disruption of the homeostasis of the extracellular matrix in mitral valve prolapse, while in hypertrophic cardiomyopathy there are many theories, but a common mechanism is suspected. Both pathologies involving the mitral valve have genetic causes: in mitral valve prolapse, most, if not all changes, revolve around the activity of TGF-β, whereas the mutations responsible for the modifications in hypertrophic cardiomyopathy are in genes that mostly codify sarcomeric proteins.The role of cardiac imaging is vital for diagnosing both pathologies and the consequent mitral regurgitation. Three-dimensional echocardiography has an emerging role in mitral valve prolapse diagnosis and is comparable to cardiac magnetic resonance imaging in the context of this disease. Also, three-dimensional echocardiography is routinely recommended and has a high potential benefit. Cardiac magnetic resonance imaging emerges in the diagnosis of hypertrophic cardiomyopathy through an accurate measurement of characteristic features and it could possibly even evaluate the risk of sudden cardiac death.Surgery is the curative treatment for these diseases involving the mitral valve. Mitral valve repairs are suitable interventions for the couple of pathologies that induce mitral regurgitation. While mitral valve prolapse only requires mitral plasty, in hypertrophic cardiomyopathy septal myectomy and mitral valve repair are required. In addition, cutting edge techniques for treating mitral valve prolapse were developed, such as decellularized heart valve, robotic surgery and virtual valve repair simulation. Regarding future perspectives for hypertrophic cardiomyopathy, gene therapy is a promising field, directly targeting endogenous mutations in the sarcomere.High levels of TGF-β are involved in the pathogenicity of mitral valve prolapse◊ Sarcomeric protein mutations are mostly incriminated for the occurrence of hypertrophic cardiomyopathy◊ An accurate description and a better understanding of the process of leaflet elongation will be essential in establishing new therapies for the treatment of both diseases◊ Early diagnosis, grading and treatment of mitral regurgitation before symptomatology onset or irreversible ventricular damage lead to an excellent chance of improved quality adjusted life years◊ 3D transesophageal echocardiography is comparable to cardiac magnetic resonance regarding feasibility and accuracy of diagnosis in mitral valve prolapse◊ Three-dimensional echocardiographic assessment of patients with mitral valve prolapse is now recommended for routine examination◊ Multimodality imaging enhances the diagnosis accuracy in patients with hypertrophic cardiomyopathy and identifies the structural abnormalities in the mitral valve responsible for the presence of systolic anterior motion◊ In patients with hypertrophic cardiomyopathy and dynamic left ventricular outflow tract obstruction, transesophageal echocardiography may recognize additional concurrent organic causes of obstruction such as a subaortic membrane◊ Cardiac magnetic resonance imaging is an increasingly useful tool in diagnosing infra-clinical cases of hypertrophic cardiomyopathy◊ Personalized computational modeling for mitral valve repair along with three-dimensional ecocardiographic guidance can provide a pre-operative selection of the optimal repair technique◊ For severe cases of hypertrophic cardiomyopathy, a promising therapeutic alternative is gene therapy, using different strategies to remove mRNA mutations or to replace mutated endogenous proteins with functional ones, in this manner delaying phenotypic expression◊


Reduced myocardial perfusion has been speculated as a potential mechanism for the development and/or propagation of myocardial fibrosis in hypertrophic cardiomyopathy (HCM). This study aims to evaluate the prevalence, distribution and extent of stress-induced perfusion abnormalities and their relationship to underlying fibrosis in patients with HCM using magnetic resonance imaging.15 patients with echocardiographically diagnosed HCM have been enrolled. Cine imaging, first-pass stress perfusion imaging using vasodilator stress (Dipyridamole), and delayed gadolinium enhancement imaging were performed. Stress hypoperfusion and delayed enhancement images were assessed both quantitatively and visually using a 16-segment model. Conversion of segmental visual scoring to % of LV by volume was achieved for both hypoperfusion (HP) and late enhancement (LE) using a standardized scoring system. For quantitative assessment prospectively defined cut-offs for LE and HP were used.Maximal wall thickness ranged from 13 to 22 mm (mean 17 ± 2.6 mm). Non-ischemic pattern LE was present in 70% of patients. Perfusion abnormalities were identified on stress perfusion images in 80% of patients using visual analysis and 87% of patients using quantitative analysis. Perfusion abnormalities were predominantly subendocardial, and were regionally associated with segments containing LE (p < 0.01). Mean percent HP and mean percent LE were 17 ± 8.4% and 10 ± 9.3%, respectively by visual estimation and 20.0 ± 12.1% and 14.0 ± 7.4%, respectively by quantitative assessment. Figure These preliminary results suggest that patients with HCM have a high prevalence of stress-induced myocardial hypoperfusion as represented by reduced first-pass gadolinium enhancement during vasodilator stress. This hypoperfusion appears to extend beyond regions of established LE suggesting a potential contribution of ischemia in the development and/or propagation of myocardial fibrosis in patients with HCM.


Fluid resuscitation manages shock effectively. However, shock is not always caused by hypovolemia; various types of shock have variable volumetric reactivity. Combined echocardiography and lung ultrasound (LUS) is a new technique for assessing volume status and pulmonary edema in these patients. We report a case of unexplained acute circulatory failure and acute kidney injury (AKI) aggravated by active fluid resuscitation. We used the critical consultation ultrasonic examination (CCUE) protocol for evaluation, and successfully revived the patient with reverse fluid resuscitation.An 82-year-old man with hypertension, atrial fibrillation, and left ventricular diastolic dysfunction (LVDD) was admitted with abdominal distention and lower extremity edema. He developed symptoms of acute circulatory failure, including low blood pressure, anuria, and skin spots. After positive fluid resuscitation, the blood pressure lowered further, and moist rales were audible over both lungs.We performed bedside critical ultrasound for evaluation. The differential diagnoses based on the findings included left atrial and right heart dilatation, low cardiac output owing to reduced left ventricular ejection consequent to excessive circulatory capacity, right heart dilation, and left ventricular compression, and pulmonary edema caused by volume overload.Infusion was withheld, and tracheal intubation and mechanical ventilation were instituted to assist breathing; reverse fluid resuscitation was initiated, using continuous renal replacement therapy (CRRT) to maintain a negative fluid balance.Within 72 hours of fluid withdrawal, the blood pressure reverted to normal, symptoms of pulmonary edema were alleviated, and the circulation and tissue perfusion were restored. The symptoms of acute renal injury are relieved and allowing urine formation without support.Not all patients with acute circulatory failure require positive fluid resuscitation. Fluid balance should be closely monitored and managed. Potential intolerance to the rapid increase in volume may lead to biventricular interaction, ultimately leading to acute circulatory failure. The shock caused by volume overload should be treated with reverse fluid resuscitation. Combined echocardiography and LUS is a powerful tool for the differential diagnosis of circulatory and respiratory dysfunction. However, the etiology of shock in certain patients is complex, and various types of shock may coexist. For instance, when hypotension is associated with obstructive  or cardiogenic  causes, patients may not respond to fluids despite having a low cardiac output. In these cases, instead of optimizing hemodynamics, fluid resuscitation aggravates the shock. Fluid over-replacement may result in a variety of hazards, including acute kidney injury (AKI) and pulmonary edema among others, which may further deteriorate circulatory function.Acute circulatory failure results from an imbalance of systemic venous return and cardiac function. It causes a decrease in cardiac output, leading to a clinical syndrome of systemic organ insufficiency.We report a case of acute circulatory failure in the general ward. After routine rehydration therapy, blood pressure was further lowered and shock was aggravated.The volume status of the patient was evaluated by combining cardiac, lung, and inferior vena caval ultrasound. After these ultrasound examinations, we considered fluid overload to be the main cause of acute circulatory failure. Bedside critical ultrasound is a powerful weapon for evaluating rapid fluid responsiveness; evaluation may be performed before and after treatment.Ethical approval was not required for reporting this case. Informed consent was obtained from the patient's family.22.1The patient was an 82-year-old man, who had a history of hypertension for the past 20 years; his highest recorded blood pressure was 180/110 mmHg, and he took his oral antihypertensive drugs including telmisartan, irregularly. He also had a history of coronary heart disease for >10 years, and was taking oral antiplatelet drugs (aspirin) irregularly. He had experienced a sudden decrease of urine volume for the past 2 days, with abdominal distension and pain, followed by edema of both lower limbs, mental disorder, loss of appetite, and occasional cough and sputum; however, there was no fever or chills.2.2The patient was admitted to the emergency department of our hospital, and no urine output was noted after urethral catheterization. Following preliminary investigations, he was transferred to the Nephrology department, where physical examination revealed the following: temperature: 36 °C, heart rate: 105 beats per minute, respiratory rate: 21 breaths per minute, and blood pressure: 145/76 mmHg. The patient was unconscious, and patchy ecchymosis were visible in both arms, forearm, and right groin. The conjunctiva and lips were pale, and the respiratory sounds in both lungs were poorly audible; no wet rales were noted. The heart rhythm was irregular with well audible heart sounds, and the abdomen was distended. Muscular atrophy was noted in both lower limbs with visible tremor in the upper limbs, and the muscle power was of level 4.2.39/L, neutrophils: 71.70%, lymphocytes: 18.90%, red blood cell count: 3.17 × 1012/L, hemoglobin: 103.00 g/L, hematocrit: 0.30, and platelet count: 66.00 × 109/L. The myocardial enzyme levels were as follows: troponin T: 115 ng/L and myoglobin: 354.70 ng/mL. The initial diagnosis in the emergency department was that of acute renal failure, and he was accordingly transferred to the Department of Nephrology. He was finally diagnosed with acute renal injury, atrial fibrillation, coronary artery atherosclerotic heart disease (grade III cardiac function), lung infection, old cerebral infarction, level 3 hypertension (high risk), prostatic hyperplasia (after prostatectomy), urethral stricture, and Parkinson syndrome.The patient underwent the following tests in hospital on an emergency basis: total protein: 61.73 g/L, potassium: 6.00 mmol/L, sodium: 130.00 mmol/L, chloride: 96.00 mmol/L, anion gap: 23.90 mmol/L, urea: 65.05 mmol/L, creatinine: 756.00 μmol/L, and glucose: 6.70 mmol/L. In addition, blood analysis revealed: leukocyte count: 4.45 × 102.4He was administered diuretics, intravenous immunoglobulin, anti-infectives, and nutritional support at the Nephrology department.On day 22 of admission, his blood pressure suddenly dropped to 86/55 mmHg, with a heart rate of 107 beats per minute, dyspnea, anuria (urine volume <100 mL/d), abdominal distention, cold extremities, and blood stasis. At this time, he was considered to have shock and insufficient organ perfusion, and was administered rehydration to improve cardiac output. However, the symptoms did not improve after administration of 500 mL of fluid. The symptoms of dyspnea worsened with further decline in blood pressure.The critical-ultrasound specialists were urgently requested to perform the protocol of critical consultation ultrasonic examination (CCUE) at the bedside to evaluate the circulatory and respiratory functions Tables  and 2. TAll the above 5 conditions were indicative of volume overload. Excessive circulating fluid had aggravated the right heart failure and pulmonary edema. Therefore, under the guidance of bedside ultrasound, reverse fluid resuscitation was immediately instituted. Bedside continuous renal replacement therapy (CRRT) was initiated to promote a negative fluid balance. A volume of 800 mL of fluid was removed in 24 hours with CRRT. On the 2nd day, his blood pressure increased to 110/80 mmHg, and the tissue perfusion improved slightly. The CCUE protocol of critical ultrasound was repeated, and CRRT was administered based on the findings. We ensured that the daily fluid output exceeded input. A total volume of 3500 mL of fluid was removed within 72 hours. We can observe that the following time, with the increase of reverse fluid resuscitation, the patient's cardiac load were significantly improved, manifested as the increase of inferior vena cava variability and cardiac output, and the decrease of blood pressure and heart rate. In addition, lung ultrasound (LUS) showed that pulmonary edema also improved significantly, which may be related to the decrease of pulmonary capillary pressure.2.5The circulation stabilized, dyspnea improved, urine output was restored without support and creatinine levels were reduced to 352 μmol/L. The third session of bedside ultrasound showed a marked reduction of B-lines in both lungs, and A-lines appeared in the anterior thoracic region, and the LUS score was decreased Table , suggest3 Marik and Cavallazzi found that only about half of the patients responded to fluid resuscitation. Therefore, not all cases of hypotension, tissue hypoperfusion, and low cardiac output in septic shock is consequent to insufficient systemic circulatory blood volume. Certain complex shock syndromes may comprise ≥2 types of shock with volume overload. Excessive fluid may not be adequately ejected from the left ventricle and may add to the preload, resulting in increased left atrial filling and pulmonary circulation pressures, pulmonary interstitial or alveolar edema, right heart enlargement, and increased central venous pressures. Pulmonary edema may also be aggravated simultaneously by volume expansion. Central venous pressure (CVP) is the pressure at the end point of venous return. It not only reflects the preload of the heart, but also the afterload of venous return in the systemic circulation. Excessive CVP hinders venous reflux and may increase renal afterload. In cases where the CVP exceeds the renal venous pressure, renal perfusion decreases with aggravation of AKI. Teixeira et al confirmed that fluid balance was an independent predictor of mortality in patients with AKI. In this case, although CVP monitoring was not available in the Nephrology ward, ultrasound monitoring of the inferior vena cava demonstrated the pressure in the central vein and right atrium to a certain extent.Although the 2016 Sepsis Resuscitation Guidelines recommend fluid resuscitation for patients with confirmed septic shock,Normally, ventricular ejection is equal on both sides. The right ventricle is less tolerant to afterload pressure , so the increase in pulmonary artery pressure due to any reason may cause rapid expansion of the right ventricle. The enlarged right ventricle exerts pressure on the left ventricle through the interventricular septum, leading to the deviation of the interventricular septum towards the left ventricle; this results in the limitation of left ventricular diastolic filling, lowering the stroke volume. The CCUE protocol can differentiate shock types in order to guide treatment. In this case, the patient had signs of circulatory failure including hypotension, skin patches, and oliguria, among others. In the first session of CCUE protocol, both lungs showed diffuse B-lines, suggestive of severe pulmonary edema. Simultaneously, echocardiography showed dilatation of the right ventricle. The systolic force of the right ventricle was significantly poorer than that of the left ventricle, and was inadequate in overcoming the increase of afterload (pulmonary circulation resistance). Therefore, right ventricular enlargement resulted from severe pulmonary hypertension. In addition, in the parasternal short axis section, the enlarged right ventricle compressed the left ventricle through the interventricular septum, restricting left ventricular diastolic volumes. Despite the compensatory increase in left ventricular ejection fraction, the inadequacy in maintaining an adequate cardiac output persists; this may lead to deficient organ perfusion. Assessment of volume responsiveness prior to fluid resuscitation is an important measure in patients with circulatory failure. It is closely related to the choice of follow-up treatment and outcomes. The combined of ultrasound findings of inferior vena cava, heart, and lung with critical ultrasound examination can accurately evaluate the volume responsiveness. Barbier et al found that dynamic monitoring of inferior vena cava variability by ultrasound was an accurate predictor of volume responsiveness. In this case, the inferior vena cava was dilated and fixed, suggesting a high right atrial pressure and a low volume responsiveness.This patient with sudden shock was in a general ward, which lacked hemodynamic monitoring facilities including CVP, pulmonary arterial incarceration pressure, cardiac output, and other tools found in the intensive care unit. Therefore, the knowledge of his hemodynamics was limited. Critical ultrasound is a new technology that has been developed in recent years. It combines the pathophysiological theory of critical diseases  with ultrasound technology. It accurately evaluates the circulatory and respiratory status of critically ill patients.These ultrasound findings provided evidence of excessive volumes in the cardiopulmonary system; reverse fluid resuscitation was therefore appropriate treatment. In the first 24 hours, the volume state was maintained in negative balance by approximately 800 mL using CRRT. Repeat ultrasound examination showed improvement in several vital parameters (Table  The diagnosis of pulmonary edema on ultrasound depends on the presence of B-lines. The number of B-lines in 1 positive area (defined as at least 3 B-lines visible between 2 ribs) correlates with the severity of pulmonary edema. If the distance between 2 B-lines  is roughly 7 mm, it may be named “B7-lines,” which correlate with thickened subpleural interlobular septa; these are known as “septal rockets.” If the distance between 2 B-lines  is roughly 3 mm, and several B-lines converge, it correlates with subpleural ground-glass lesions. These are known as “B3-lines” or “ground-glass rockets” and indicate severe interstitial lung disease. The diagnostic value of LUS in pulmonary edema is higher than that of chest radiographs. Gargani et al found that the B-lines appeared earlier on ultrasound than chest radiographs in patients with acute heart failure; this may be used as an early warning indicator. The CCUE protocol integrates cardiac, pulmonary, and inferior vena caval ultrasound to evaluate critically ill patients. It rapidly identifies the cause of acute circulatory or respiratory failure, and evaluates the volume status and responsiveness, guiding further treatment.Ultrasound is an excellent examination tool in patients who cannot be transported to the imaging department, including older adults, those with multiple organ failure, and those on bedside mechanical ventilation or CRRT. LUS is useful in diagnosing the cause of dyspnea. Lichtenstein performed lung ultrasonography in 6 common diseases causing dyspnea, namely, pulmonary edema, chronic obstructive pulmonary disease, asthma, pulmonary embolism, pneumothorax and pneumonia in the intensive care unit, to confirm its diagnostic accuracy.4In patients with symptoms of shock including decreased blood pressure, increased heart rate, and oliguria, the volume status should be determined and volume responsiveness should be assessed prior to fluid resuscitation. In critically ill and non-ambulatory patients, bedside ultrasound may provide a clearer and rapid understanding of the patient's condition; it may also allow prompt comparison of treatment outcomes before and after treatment. It may also reduce the risk of other complications, and shows promise in widespread application in the future. Cumulative evidence from further reports is needed to confirm our findings.Resources: Haotian Zhao, Zekai WangSupervision: Heling Zhao.Visualization: Haotian Zhao, Ling Long, Zekai Wang.Writing – original draft: Haotian Zhao, Yaru Yan.Writing – review & editing: Ling Long, Heling Zhao.


Abnormal invasive hemodynamics after transcatheter aortic valve replacement (TAVR) is associated with poor survival; however, the mechanism is unknown.Diastolic dysfunction will modify the association between invasive hemodynamics postTAVR and mortality.Patients with echocardiographic assessment of diastolic function and postTAVR invasive hemodynamic assessment were eligible for the present analysis. Diastology was classified as normal or abnormal (Stages 1 to 3). The aorto‐ventricular index (AVi) was calculated as the difference between the aortic diastolic and the left ventricular end‐diastolic pressure divided by the heart rate. AVi was categorized as abnormal (AVi < 0.5 mmHg/beats per minute) or normal (≥ 0.5 mmHg/beats per minute).P < .001). All‐cause mortality was 46% in the abnormal vs 31% in the normal AVi group (P < .001). Adjusted hazard ratio (HR) for AVi < 0.5 mmHg/beats per minute vs AVi ≥0.5 mmHg/beats per minute for intermediate‐term mortality was . This association was the same among those with normal diastolic function and those with diastolic dysfunction (P for interaction = .35).From 1339 TAVR patients, 390 were included in the final analysis. The mean follow‐up was 3.3 ± 1.7 years. Diastolic dysfunction was present in 70.9% of the abnormal vs 55.1% of the normal AVi group (Diastolic dysfunction is prevalent among TAVR patients. Low AVi is an independent predictor for poor intermediate‐term survival, irrespective of co‐morbid diastolic dysfunction. AViaorto‐ventricular indexCIconfidence intervalHRhazard ratioTAVRtranscatheter aortic valve replacement1Hemodynamic assessment was initially developed as a supplemental tool to assess for paravalvular aortic regurgitation after transcatheter aortic valve replacement (TAVR).22.1clinicaltrials.gov, NCT01368250).All patients undergoing TAVR at the University of Bern were consecutively enrolled in an institutional database that is part of the Swiss TAVI Registry  peak tricuspid regurgitation velocity > 2.8 m/s.All patients underwent a transthoracic echocardiogram within 3 months before TAVR. During the echocardiogram, at least three consecutive heart beats were recorded and averaged for each parameter. Echocardiogram loop and still frames were analyzed at a workstation for offline analysis . According to current American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines, the following variables were required for assessment of diastolic dysfunction (see flow diagram from previous publication): (a) annular e' velocity ; (b) average E/e' ratio > 14; (c) left atrial maximum volume index >34 mL/m2.3A multidisciplinary heart team of cardiac surgeons, interventional cardiologists, imaging, and heart failure specialists decided on treatment strategy and suitability for TAVR, which was performed according to current guidelines and standard approaches.After the intervention, all patients were monitored for at least 48 hours. Laboratory examination and a 12‐lead electrocardiogram were routinely performed immediately after the procedure and daily thereafter. In all patients, echocardiogram was performed before discharge.2.4Standardized clinical follow‐up was performed at 30 days, 1 year, and 5 years after TAVR. Telephone interviews, documentation from referring physicians, and hospital discharge summaries were used to ascertain clinical endpoints. All suspected adverse events were independently adjudicated according to the criteria by the valve academic research consortium‐2.2.5P values were derived from student's t tests for continuous and chi‐square tests for categorical variables comparing the two groups. The cumulative incidence of the primary and secondary endpoints was estimated by the Kaplan‐Meier method. Patients were censored at the event of interest, time of last contact, or the maximal follow‐up time. Cox regression was used to compare time‐to‐event data between groups. Crude hazard ratios (HR) were generated with  with P values from Wald chi‐square tests. Adjusted HR (95% CI) included all variables with a P value <.10 from the univariable analysis into the multivariable model.Continuous data are reported as mean ± SD and categorical variables as the number of patients and percentage. P values <.05 were considered statistically significant.All analyses were performed with Stata version 14.2 . Two‐sided 3Between August 2007 and December 2015, 1339 patients were enrolled in the TAVI registry. Seven hundred and seventy underwent detailed echocardiographic assessment and after excluding an additional 387 patients due to inability to grade diastolic dysfunction, lack of postTAVR invasive assessment, or moderate to severe paravalvular aortic regurgitation, 390 were included in the final cohort Figure . The meaP < .001, Table P < .001). Mean total arterial compliance was the same in both groups. Intra‐procedural hemodynamic variables are provided in Table One hundred and eighty‐nine patients (48.5%) were categorized as abnormal (AVi < 0.5) and 201 patients (51.5%) as normal (AVi > 0.5). There were no differences in baseline characteristics, except that the abnormal hemodynamics group had a higher prevalence of peripheral vascular disease and higher estimated surgical risk (Table P < .001) (Table P = .018).Diastolic dysfunction was present in 70.9% of the abnormal AVi group vs 55.1% of the normal AVi group (1) Table . DiastolP = .001) . The multi‐variable association between low vs normal AVi was . Among those with diastolic dysfunction, all‐cause mortality was 59% in the AVi < 0.5 vs 44% in the AVi ≥0.5 group (P = 0.006). The multi‐variable association between low vs normal AVi was   and among those with elevated baseline filling pressures the association was   Baseline diastolic dysfunction was prevalent among TAVR patients. (b) Postimplantation AVi < 0.5 mmHg/beats per minute was an independent predictor for poor intermediate‐term survival. (c) Abnormal invasive hemodynamics was associated with poor prognosis irrespective of baseline diastolic dysfunction. We previously theorized that each component of the AVi would have clinical significance. For example, a low aortic diastolic pressure could represent unrecognized paravalvular aortic regurgitation, poor systemic flow, and/or poor arterial compliance. An elevated left ventricular end‐diastolic pressure could represent left ventricular systolic dysfunction and/or diastolic dysfunction. An elevated heart rate could represent poor systemic flow (since heart rate is inversely related to stroke volume) and/or background medical therapy. Therefore, the AVi is more than just an assessment of diastolic dysfunction, which was born out in the study findings.These findings confirm our previous observation of an association between abnormal hemodynamics and poor survival, but this time in a larger independent cohort. The current analysis leveraged the Bern TAVI registry, which represents the largest published work on diastology and TAVR. Diastolic dysfunction was prevalent among all patients but especially among those with abnormal hemodynamics; however, pre‐operative diastolic dysfunction did not modify the association between abnormal AVi and intermediate‐term survival. We found no evidence for a difference in total arterial compliance between groups, which was another potential mechanism for the hazardous association.Moderate to severe paravalvular aortic regurgitation has consistently been shown to be associated with poor survivalWe previously reported that diastolic dysfunction Stage 3 was the strongest predictor for 1 year mortality. Optimal management of left ventricular diastolic dysfunction among TAVR patients is not well known.Limitations of the current analysis include: (a) Abnormal hemodynamics was present in approximately one‐fifth of our derivation cohort vs approximately one‐half of patients in the current cohort. The reason for this difference is unknown. Aortic diastolic blood pressure was the same between the two cohorts with abnormal hemodynamics; however, the Bern TAVI registry was associated with a higher left ventricular end‐diastolic pressure and heart rate. This may reflect differences in background/procedural medical therapy; however, this information was not available in either registry. (b) Patients with mitral annular calcification, atrial fibrillation, previous pacemaker or surgical mitral valve were excluded from the current study. This could have resulted in unintended selection bias; however, these characteristics were included in our development cohort.5In summary, invasive hemodynamic assessment after TAVR can be used to risk stratify patients. There was a high prevalence of diastolic dysfunction among TAVR patients. AVi < 0.5 mmHg/beats per minute was associated with poor intermediate‐term survival, and baseline diastolic dysfunction did not modify this association.Dr Anthony Bavry has received honoraria from the American College of Cardiology and Edwards Lifesciences (significant); Dr Taishi Okuna has receive lecture fees from Abbott (modest); Dr Stephan Windecker received research and educational grants to the institution from Abbott, Amgen, Bayer, BMS, Biotronik, Boston Scientific, CSL Behring, Edwards, Medtronic, Polares and Sinomed; Dr Thomas Pilgram received research grants to the institution from Biotronik, Boston Scientific, Edwards Lifesciences; speaker fees from Biotronik and Boston Scientific; consultancy for HighLifeSAS.Figure S1 Flow diagram of study cohortClick here for additional data file.Figure S2 Survival analysis among subjects with low vs normal Aorto‐Ventricular index (AVi)Click here for additional data file.Table S1 Clinical outcomesClick here for additional data file.