Percutaneous mitral valve repair in acute mitral regurgitation: case report and review of the literature

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INTRODUCTION
Percutaneous repair of mitral regurgitation (MR) with the MitraClip device (Abbott Vascular, Abbott Park, Illinois, USA) is an established therapeutic option for patients with prohibitive surgical risk and anatomically suitable mitral valve (MV) [1] . Implanted in over 100,000 patients worldwide, MitraClip procedure is safe and boasts a highly favourable risk-benefit ratio. While the impact of percutaneous MV repair on outcomes in chronic severe symptomatic MR has been evaluated for years in detail, data regarding the use of percutaneous edge-to-edge procedure in patients with severe acute MR are scarce and limited to case reports or small-size registries. Acute MR is a complex and heterogeneous pathology, with severe hemodynamic consequences and extremely adverse outcomes [2] . Traditionally, in most cases, after hemodynamic stabilization, the definitive treatment is surgical intervention. Nowadays, the MitraClip device is proving to be a valuable therapeutic option in high-risk patients.
Hereby, we present a case of acute severe ischemic mitral regurgitation successfully treated with MitraClip procedure.

CASE DESCRIPTION
We report the case of an 82-year-old female patient, who presented to emergency department for chest pain lasting for 72 h. The EKG revealed a latecomer lateral ST-elevation myocardial infarction, with STdepression in V1-V4, ST-elevation and q waves in V7-V9. She had a history of arterial hypertension, rheumatoid arthritis, thalassemia minor, and radiotherapy-treated tongue cancer.
A bedside echocardiogram showed a left ventricular ejection fraction (LVEF) of 40% due to akinesia of posterior and lateral walls, normal left ventricular and atrial dimensions, mild MR, normal right ventricular function and size. Urgent coronary angiography was performed and showed a flow-limiting stenosis in the proximal tract of a dominant circumflex coronary artery. The coronary lesion was treated with balloon angioplasty and implantation of two drug-eluting stents. A severe no-reflow followed and prompted the use of intraortic balloon pump (IABP) for hemodynamic stabilization and the intracoronary injection of nitroprusside and adrenaline. The patient was transferred to Coronary Care Unit and remained hemodynamically stable for the subsequent 24 h.
Then, a sudden hemodynamic collapse occurred, with pulmonary congestion and hypotension requiring intubation and high-dose vasopressors. Trans-thoracic and trans-esophageal echocardiogram (TEE) showed acute severe MR with eccentric jet directed towards the posterior wall of left atrium, due to extreme tethering of the posterior leaflet with partial posteromedial papillary muscle rupture and pseudoprolapse of the anterior leaflet [ Figure 1]. The patient was deemed inoperable due to prohibitive surgical risk (age, subacute myocardial infarction with no-reflow injury, upper thorax radiotherapy, dual antiplatelet therapy, hemodynamic instability; STS score -risk of mortality: 66.6%; Euroscore II: 43.52%) and despite the highly challenging morphology of valvular disease, a salvage MitraClip procedure was the only feasible path. The mechanism of MR was complex: a Carpentier type IIIC (asymmetric systolic restriction) with a main jet located at A3-P3 extended to the medial section of A2-P2, plus a partial posteromedial papillary muscle rupture implicating an additional risk of mechanical complications, a coaptation gap > 10 mm, a posterior leaflet of 9 mm, but without calcifications at the grasping zone and with a suitable MV area ( > 4 cm²) [3] .
The patient underwent an urgent percutaneous edge-to-edge procedure under general anaesthesia, with IABP and vasopressor support, and using fluoroscopic and TEE guidance. An XTR Clip was first implanted in A3-P3 position with residual moderate MR and mean gradients of 3 mmHg [ Figure 2], then an NTR Clip was used in A2-P2 position with a resulting minimal MR and mean gradients of 4 mmHg [ Figure 3].
The patient's hemodynamics progressively improved, and she was successfully weaned off mechanical ventilation and pharmacological support. Her post-operative recovery was uncomplicated and the patient was discharged on the tenth post-procedural day with residual mild MR and mean gradients of 5 mmHg [ Figure 4].

DISCUSSION
Acute MR is a medical and surgical emergency. Indeed, differently from chronic valvular diseases, acute MR occurs suddenly in normal sized hearts, without time for adaptative left atrial and ventricular enlargement. This results in a rapid increase of left atrial pressure with consequent pulmonary congestion  and, despite initial hyperdynamic ventricular contraction, a risk of progressive reduction of cardiac output with hypotension and peripheral hypoperfusion [4] . Thus, patients with acute MR usually present with severe dyspnea, and slip towards cardiogenic shock.
Timely diagnosis may be insidious, due to nonspecific clinical pattern and equalization of left ventricular and atrial pressures leading to a soft or absent murmur [2] . Even pulmonary edema can be atypical with unilateral involvement if the regurgitant jet is eccentrically directed into either the right or the left pulmonary veins [2] . Echocardiography is key to diagnosis and proper management of the different causes of this disease [5] .
Traditional management involves medical stabilization and surgical intervention, with a timing strictly related to the specific etiology of valve dysfunction [6] . MitraClip device has emerged as a new therapeutic alternative which is promising and potentially life-saving.
In the following sections, the main aspects of acute MR will be analysed with a focus on the amenability and use of percutaneous edge-to-edge repair technique in this condition.

Etiology
Identifying the precise mechanism and cause of acute MV disease is fundamental to tailor the most appropriate therapeutic strategy for each patient. Acute MR counts few mechanisms and many possible causes, as detailed in Table 1. First of all, the distinction between structural damages and functional alterations is fundamental, because organic causes always require repair, whereas functional causes may improve after targeting the underlying myocardial infarction, ischemia, or systolic dysfunction [5] .
One major organic cause is chordal rupture which may occur in an otherwise totally normal valve or in a MV affected by Barlow's disease or fibroelastic deficiency.
Device-related MR is a rare yet possible complication of left ventricular mechanical support devices due to catheter impingement in the chordal apparatus or leaflet tissue [7] . Iatrogenic MR is also reported after percutaneous mitral valvotomy for rheumatic mitral stenosis, albeit unlikely if patients are adequately selected.
Infective endocarditis can cause leaflet perforation and tears, papillary muscle and chordal rupture or may reduce systolic coaptation due to masses or abscesses interfering with leaflets' apposition. "Carpentier types" refer to expanded Carpentier classification [3] Extremely rare etiologies include chest traumas, systemic inflammatory diseases or acute rheumatic fever which remains a serious concern in endemic areas [8,9] .
Ischemic papillary muscle rupture is another major cause of acute massive MR, with more frequent involvement of the posterior papillary muscle during inferior myocardial infarctions.
Acute myocardial ischemia or infarction may cause acute functional MR with systolic symmetrical or asymmetrical leaflet tethering, due to global or regional ventricular systolic dysfunction.
Another functional cause of MR is systolic anterior motion (SAM) of mitral leaflets in hypertrophic obstructive cardiomyopathy or Takotsubo cardiomyopathy [2] .

Diagnosis of acute MR
Echocardiography is essential for diagnosis. As opposed to chronic MR, left atrial and ventricular sizes are usually normal in acute MR, except for preexisting conditions influencing chambers' dimension, compliance and hemodynamic tolerance. For instance, patients with a history of chronic MR and preserved ventricular systolic function have enlarged cardiac volumes and tolerate the further volumetric increase better than patients with normal sized hearts or with preexisting reduced LVEF. Color Doppler may underestimate the severity of MR, owing either to rapid equalization of left atrial and ventricular pressures or to an eccentric direction of the regurgitant jet with "Coanda" effect. Consequently, the use of color Doppler-based quantitative measures such as regurgitant volume and effective regurgitant orifice area may be misleading and even challenging, due to severe acute congestive heart failure with tachycardia. Vena contracta width and continuous wave Doppler signal represent reliable semiquantitative tools to quickly evaluate the significance of MR. A triangular and dense continuous wave Doppler curve supports the diagnosis of acute MR. It mirrors the rapid decline in late systolic velocity as a consequence of the abrupt increase in left atrial pressure. Systolic pulmonary venous flow reversal in one or both pulmonary veins can be found but tachycardia or atrial fibrillation can mask these findings. Any measure or value should be interpreted in the clinical context, as patients with acute heart failure and acute MR may appear to have only moderate MR when assessed by semi-quantitative and quantitative methods. Indeed, an acute significant MR should be suspected in patients with a clinical pattern of acute heart failure, with evidence of hyperdynamic LV without systolic or diastolic dysfunction, and with anatomic imaging of MV lesions [10,11] .
Trans-thoracic echocardiography is the first-line examination in the assessment of acute dyspnea, feasible at bedside and sufficient to raise the clinical suspicion, but often inconclusive regarding the identification of the mechanism of MR, the evaluation of the MV anatomy and preoperative planning, which all require TEE. As such, three-dimensional (3D) echocardiography should always be adopted, as it provides anatomical details not detectable with two-dimensional (2D) imaging, enabling a dynamic and comprehensive assessment of MV tissue, and seizes dataset for off-line multiplanar reconstructions [12] .

Mechanism and cause of MR
The first step of echocardiographic evaluation of MR mechanism is the distinction between organic/ structural damage and functional alteration of MV [ Table 1]. Close assessment of leaflet motion, anatomic lesions and finally the Color Doppler-based evaluation of convergence area and regurgitant jets are required.
A structural lesion with normal leaflet motion is generally due to a leaflet perforation. In this case, TEE should evaluate the position, shape and dimensions of the perforation, detect any sign suggestive of endocarditis, such as masses, vegetations or abscesses and explore mitral-aortic junction, left ventricular outflow tract and the position of other intracardiac devices. Indeed, an ambitious combined percutaneous procedure of MitraClip plus occluder would be contraindicated in the presence of active endocarditis, and an accurate preoperative planning should take into account the risk of iatrogenic obstruction of ventricular outflow or interference with proximally-located prostheses [13] .
Leaflet flails and prolapse are categorised as Carpentier type II mechanism and occur through sudden rupture of chordae tendineae or papillary muscles due to many possible causes [11] . Myxoid degeneration or Barlow's disease is a major cause of chordal rupture and remains extremely challenging for percutaneous repair due to altered anatomy, including extensive leaflet thickening, multi-segmental prolapse, elongated or fused chordae tendineae, diffuse calcifications and annular dilatation [14] . Beyond procedural challenges, the main issue is the balance between a relevant residual MR due to the highly mobile and redundant leaflets and a resultant iatrogenic mitral stenosis owing to extensive grasping with multiple clips. However, the introduction of MitraClip XTR device, with a wider reach and longer clip arms than NTR, has broadened the "graspable" MV anatomies, including Barlow's disease, as documented by a few case series [15][16][17] . Nonetheless, myxoid degeneration appears early in life and patients are usually referred for surgery due to young age and low risk, on the contrary fibroelastic deficiency affects elderly people with significantly different operative risk. In fibroelastic deficiency MV is characterized by impaired production of connective tissue and shows thin leaflets, prolapse of single segments, and rupture of thin chordae with limited flail width [14] . MitraClip has been shown to be feasible and safe in this type of MV anatomy, even in octogenarians, but care should be taken in cases of fragile leaflet tissue due to the risk of grasping-related leaflet tears or lacerations [18] .
Papillary muscle rupture is a severe, albeit rare, mechanical complication of acute myocardial infarction. This anatomic lesion is challenging given the large flail width and flail gap with frequent commissural localization requiring an extensive grasping with a concomitant high risk of chordal entanglement [19] . As a papillary muscle head may mimic an endocarditic mass, clinical context should guide the differential diagnosis [20] . Moreover, infective endocarditis itself may be causative of chordal rupture and papillary muscle laceration, in the presence of typical echocardiographic criteria such as vegetations and abscesses [21] .
Among functional alterations of MV, the main cause of acute MR is myocardial ischemia. Indeed, in the very acute phase of myocardial infarction, even modest valve tenting due to regional and/or global left ventricular dysfunction may result in hemodynamically-significant MR [22] . Echocardiography should be performed to assess the presence of wall motion abnormalities and myocardial scarring, and the "symmetry" of mitral leaflets with respect to their point of coaptation. In cases of asymmetric tenting, it is generally the posterior leaflet that tethers while the anterior leaflet shows a ''pseudoprolapse'' motion. The MR jet is eccentric and oriented against the posterior wall of left atrium. In cases of symmetric tethering, both leaflets are tented but the coaptation point is displaced apically at the leaflets' tips, and the jet is typically central [23] .
An infrequent cause of acute MR is SAM of mitral leaflet, which represents a life-threatening condition and may result also in critical left ventricular outflow tract obstruction. Hypertrophic obstructive cardiomyopathy is the main pathology associated with SAM and is characterized by abnormalities of MV and subvalvular apparatus, such as malpositioned papillary muscles, elongated chordae and thickened leaflets [24] . These anatomic features may impact on transmitral gradients and residual MV area after MitraClip procedure [25] . SAM with left ventricular outflow obstruction may occur in several other conditions such as Takotsubo cardiomyopathy, hypertensive hypertrophic cardiopathy, hypovolemia, severe bleeding, sepsis, vasodilatation, sympathetic activation, pericardial tamponade, after aortic valve replacement, and after surgical mitral valve repair [25] . In these acute conditions a transcatheter edge-to-edge technique certainly sounds appealing to target both MR and hypotension.
Finally, rheumatic heart disease is commonly regarded as a contraindication to MitraClip procedures, owing to high risk of mitral stenosis. However, a recently published case report has shown the feasibility of percutaneous MV repair in a rheumatic MV with baseline mean gradients inferior to 4 mmHg [26] . Accurate measurement of MV area through 3D-based multiplanar reconstruction, evaluation of trans-mitral mean gradients and exclusion of calcifications at the grasping area are essential to decision-making and preoperative planning.
As outlined above, absolute anatomic limitations are very few. Hahn [27] listed the echocardiographic features associated with ideal and challenging anatomies and highlighted a few relative contraindications. The absolute contraindications include severe and extended calcifications of the grasping zone, short leaflet length (< 7 mm) and small baseline MV area (< 3.5 cm²) [15] .
The vast majority of cases occurred as complications of acute myocardial infarction, due to either ischemic leaflet tethering or papillary muscle ruptures (more often the posteromedial one). A primary PCI was always performed, except for late presentations due to the likely risk of reperfusion injury of already necrotic walls. The hemodynamic status was generally critical with evidence of cardiogenic shock and pulmonary edema requiring intubation, inotropes and mechanical support, mainly IABP and only in few cases veno-arterial extracorporeal membrane oxygenation. The Heart Team's decision to proceed with MitraClip was primarily guided by the high surgical risk due to hemodynamic instability, acute/subacute ischemia, dual antiplatelet therapy, advanced age or comorbidities in a few cases, and the favourable riskbenefit balance of percutaneous edge-to-edge approach. Hemodynamic stabilization and likeliness of MR improvement with revascularization or medical therapy were the main determinants of the timing of procedure. One to three clips were deployed with an almost complete procedural success, due to significant reduction of MR, huge reduction of left atrial pressures and increase of cardiac output. Haberman et al. [42] reported one case of posterior leaflet tear during a second clip implantation, followed by urgent MV surgery and lastly by patient death. Early outcomes were promising, with high survival rates, sustained reduction of MR grade and improved functional class. These results are even more reassuring if compared with surgical ones; in a multicentre surgical registry of 279 patients treated with emergency surgery for acute severe MR, due to myocardial infarction, acute endocarditis or degenerative MV disease, the 30-day mortality was 22.5% with worse survival rates in case of acute myocardial infarction, endocarditis, shock, coronary artery disease and systolic dysfunction [44] . Despite the evidences seem extremely optimistic regarding outcomes of MitraClip in almost every acute setting, a publication bias has to be recognized, and the interventionalists' and imagers' experience should be considered during Heart Team decision-making. Certainly, MitraClip shows several advantages over surgery. Firstly, MitraClip is safe and does not preclude a delayed surgical procedure in case of failure, thus a "bridge" procedure may be always attempted without significant additional risks. Secondly, percutaneous procedures permit to avoid the cardiopulmonary bypass and the associated systemic inflammatory storm and myocardial oxidative stress. Furthermore, transcatheter procedures do not cause abnormal motion of the right ventricle or interventricular septum, which may impact on long-term LV performance [43] .

Decision-making and management
We propose a flow-chart that may be helpful for acute MR decision-making and management [ Figure 5].
Once acute MR is diagnosed, the initial goal is hemodynamic stabilization through inotropes/vasopressors and temporary mechanical circulatory supports (IABP, Impella and extracorporeal membrane oxygenation) Percutaneous edge-toedge mitral valve repair for the treatment of acute mitral regurgitation complicating myocardial infarction: A single centre experience Adamo et al. [40] AMI without papillary muscle rupture: in cases of cardiogenic shock, intravenous diuretic therapy and non-invasive/invasive ventilation for massive pulmonary edema with acute respiratory distress. Hypertensive or normotensive patients benefit from afterload reduction with intravenous vasodilator therapy, which reduces MR, diminishing pulmonary congestion and increases forward cardiac output [6] .
Then, an accurate trans-esophageal echocardiographic characterization of acute MR is needed to tailor the subsequent actions. The finding of a Carpentier type I lesion, as a leaflet perforation, should lead to exclude an active acute endocarditis, which represents a contraindication for MitraClip procedure and an indication for cardiac surgery [45] . Clinical context and laboratory tests are pivotal to distinguish active endocarditic processes from a treated state, for which percutaneous interventions are not contraindicated. Careful history taking is sufficient to exclude a device-related (transcatheter prosthetic aortic valves and intracardiac left ventricular assist devices) mechanism.
A Carpentier type II mechanism (leaflet prolapse/flail, rupture of chordae or papillary muscle) warrants a wide differential diagnosis between multiple potential causes. As already reported for Carpentier type I, active endocarditic processes should be excluded, as well. Myocardial ischemia or infarction may cause partial or complete rupture of a papillary muscle and could be targeted with medical therapy or percutaneous myocardial revascularization, before treating the MV lesion. A case-by-case judgement is fundamental and should consider the presence of ongoing myocardial ischemia, the timing of onset of myocardial infarction, the extension of coronary artery disease, the type of MV lesion (partial versus complete rupture), and the differential burden between ischemic and valvular diseases. Primary percutaneous coronary intervention for an ST-elevation myocardial infarction is always indicated, except for delayed infarctions without evidence of ongoing ischemia, as they would not yield significant benefits from revascularization and yet be complicated by reperfusion injury [46,47] . Early surgical intervention is crucial for complete papillary muscle rupture, although partial rupture may benefit from percutaneous revascularization or a brief period of stabilization [48] . When acute MR is caused by chordal rupture in MV affected by fibroelastic deficiency or Barlow's disease, anatomic evaluation has a central role to ensure the feasibility of an eventual MitraClip procedure, as already explained in previous paragraphs.
The observation of a Carpentier type III mechanism is related to regional or global LV systolic dysfunction. Medical therapy and percutaneous coronary intervention can acutely reduce the degree of ischemic MR, and an earlier reperfusion time is associated with greater reduction in MR severity [49] . Thus, if hemodynamic conditions are stable after revascularization or medical therapy implementation, a "wait and see" strategy may be undertaken with close and constant monitoring.
A Carpentier type IV mechanism, namely a SAM of mitral leaflets, observed in hypertrophic and Takotsubo cardiomyopathies, represents an insidious cause of acute MR. Echocardiographic diagnosis is exceedingly important, as vasodilators, inotropes or IABP worsen the clinical and hemodynamic status. Beta-blockers, volume expansion, inotrope discontinuation, afterload augmentation with vasopressors Figure 5. Proposed flow-chart for acute MR decision-making and management. "Carpentier type" refers to Carpentier classification of MR mechanisms, as exposed in Table 1. AE: acute endocarditis; C.t.: Carpentier type; MR: mitral regurgitation; MV: mitral valve; PCI: percutaneous coronary intervention; TEE: trans-esophageal echocardiography; TTE: trans-thoracic echocardiography and lastly mechanical circulatory supports (Impella and extracorporeal membrane oxygenation) are the weapons to turn to [50,51] .
After the initial phases of echocardiographic diagnosis, hemodynamic stabilization, medical therapy implementation and eventually percutaneous coronary revascularization, it is time for Heart Team assessment. Interventionalists, cardiac surgeons, imagers, intensivists and heart failure specialists must meet to tailor the best therapeutic pathway, weighing all clinical and anatomical factors: age, comorbidities, hemodynamic status, response to medical therapy, MR mechanism, surgical risk, other surgical targets and single centre's experience. In cases of low surgical risk, presence of an indication for concomitant cardiac surgery and organic MV disease, cardiac surgery is the first-choice treatment. Differently, in our opinion, MitraClip should be always attempted in a stepwise approach, as it is a safe procedure and does not preclude a delayed surgical intervention. Even in low-risk patients undergoing isolated MV surgery with a low probability of surgical repair, MitraClip may be attempted, above all in high-volume centers. Eligibility for percutaneous edge-to-edge procedure requires only three conditions: possibility to grasp and approximate the leaflets, low risk of MV stenosis, and good-quality TEE imaging [19] .

CONCLUSION
Acute MR is a life-threatening condition, traditionally treated as a medical and surgical emergency. Percutaneous edge-to-edge repair of MV is a safe and effective therapeutic option, does not preclude delayed cardiac surgery and is potentially able to solve almost any type of MV disease, with very few contraindications. Echocardiographic identification of the precise valvular lesion and Heart Team evaluation are pivotal to tailor the best therapeutic pathway for each patient. Literature confirms optimal results of MitraClip in acute MR, but further studies are warranted to shed light on feasibility and limitations of this powerful procedure.