Stages of Chronic AR Stage Definition Valve Anatomy Valve Hemodynamics Hemodynamic Consequences Symptoms A At risk of AR BAV (or other congenital valve anomaly) Aortic valve sclerosis Diseases of the aortic sinuses or ascending aorta History of rheumatic fever or known rheumatic heart disease IE AR severity: none or trace None None B Progressive AR Mild to moderate calcification of a trileaflet valve BAV (or other congenital valve anomaly) Dilated aortic sinuses Rheumatic valve changes Previous IE Mild AR: Jet width <25% of LVOT Vena contracta <0.3 cm Regurgitant volume <30 mL/ beat Regurgitant fraction <30% Angiography grade 1 Moderate AR: Jet width 25% 64% of LVOT Vena contracta 0.3 0.6 cm Regurgitant volume 30 59 mL/ beat Regurgitant fraction 30% to Angiography grade 2 Normal LV systolic function Normal LV volume or mild LV dilation None C Asymptomatic severe AR Calcific aortic valve disease Bicuspid valve (or other congenital abnormality) Dilated aortic sinuses or ascending aorta Rheumatic valve changes IE with abnormal leaflet closure or perforation Severe AR: Jet width 65% of LVOT Vena contracta >0.6 cm Holodiastolic flow reversal in the proximal abdominal aorta Regurgitant volume 60 mL/ beat Regurgitant fraction 50% Angiography grade 3 to 4 In addition, diagnosis of chronic severe AR requires evidence of LV dilation and mild to moderate LV dilation (LVESD <50 mm) C2: Abnormal LV systolic function with depressed LVEF ( 55%) or severe LV dilation (LVESD >50 mm or ) None; exercise testing is reasonable to confirm symptom status D Symptomatic severe AR Calcific valve disease Bicuspid valve (or other congenital abnormality) Dilated aortic sinuses or ascending aorta Rheumatic valve changes Previous IE with abnormal leaflet closure or perforation Severe AR: Doppler jet width 65% of LVOT Vena contracta >0.6 cm Holodiastolic flow reversal in the proximal abdominal aorta Regurgitant volume 60 mL/ beat Regurgitant fraction 50% Angiography grade 3 to 4 In addition, diagnosis of chronic severe AR requires evidence of LV dilation Symptomatic severe AR may occur with normal systolic function (LVEF >55%), mild to moderate LV dysfunction (LVEF 40% to 55%), or severe LV dysfunction (LVEF Moderate to severe LV dilation is present Exertional dyspnea or angina or more severe HF symptoms AR indicates aortic regurgitation; BAV, bicuspid aortic valve; ERO, effective regurgitant orifice; HF, heart failure; IE, infective endocarditis; LV, left ventricular; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; and LVOT, left ventricular outflow tract. CLINICAL STATEMENTS AND GUIDELINES 4.3. Chronic AR 4.3.1. Diagnosis of Chronic AR Recommendations for Diagnostic Testing of Chronic AR Referenced studies that support the recommendations are summarized in Online Data Supplement 14. COR LOE Recommendations In patients with signs or symptoms of AR, TTE is indicated for assessment of the cause and severity of regurgitation, LV size and systolic function, prognosis, and timing of valve In patients with a BAV or with known dilation of the aortic sinuses or ascending aorta, TTE is indicated to evaluate the presence and severity In patients with moderate or severe AR and suboptimal TTE images or a discrepancy between clinical and TTE findings, TEE, CMR, or cardiac catheterization is indicated for the assessment of LV systolic function, systolic and diastolic volumes, aortic size, and AR severity.20 25 Synopsis TTE provides diagnostic information about the etiology and mechanism of AR (including valve reparability), se- verity of regurgitation, morphology of the ascending aorta, and LV response to the increases in preload and afterload. Imaging with TEE, CMR, or aortic angiogra- phy provides additional information when needed. Recommendation-Specific Supportive Text 1. Although qualitative measures of AR severity are adequate in many situations, when AR is signifi- cant (Stages B and C), quantitative measures of regurgitant volume and effective regurgitant orifice (ERO) area1 are better predictors of clini- Measures of LV systolic function (LVEF or fractional shortening) and LV end-systolic dimension (LVESD) or LV end-systolic volume are predictive of the development of HF symptoms or death in initially asymptomatic patients (Stages B and C1) and are significant determinants of survival and functional results after surgery in asymptomatic and symptomatic patients (Stages Symptomatic patients (Stage D) with normal LVEF have a significantly better long- term postoperative survival rate than those with depressed systolic function. 2. Auscultation has high specificity for detecting AR but low sensitivity and diagnostic accuracy.27 TTE can identify AR in patients who have been deemed to be at risk on the basis of the presence of known aortic dilation or a condition associated with abnormal aortic valve function, such as a BAV. 3. TTE and CMR are useful for evaluating patients in whom there is discordance between clinical assessment and severity of AR by TTE or when TTE images are suboptimal. CMR imaging pro- vides accurate and reproducible measures of regurgitant volume and regurgitant fraction in patients with AR, as well as assessment of aortic morphology, LV volume, and LV systolic func- tion. Cardiac catheterization with LV and aortic angiography, as well as quantitation of regurgi- tation severity, is another option.20 25,28 30 4.3.2. Medical Therapy Recommendations for Medical Therapy of Chronic AR Referenced studies that support the recommendations are summarized in Online Data Supplement 14. COR LOE Recommendations In asymptomatic patients with chronic AR (Stages B and C), treatment of hypertension (systolic blood pressure >140 mmHg) is In patients with severe AR who have symptoms and/or LV systolic dysfunction (Stages C2 and D) but a prohibitive surgical risk, GDMT for reduced LVEF with ACE inhibitors, ARBs, and/or sacubitril/valsartan is Synopsis There is no evidence that vasodilating drugs reduce se- verity of AR or alter the disease course in patients with significant AR in the absence of systemic hypertension. Recommendations for GDMT for hypertension and HF apply to patients with chronic asymptomatic AR, as for the general population. Recommendation-Specific Supportive Text 1. Severe AR is associated with a wide pulse pres- sure, such that systolic blood pressure is higher than in patients without AR even when systemic vascular resistance is normal. Transaortic stroke volume increases further with medications that lower heart rate, such as beta blockers, which may result in a paradoxical apparent increase in blood pressure. Vasodilating drugs, such as ACE inhibitors or ARBs, do not affect heart rate and thus may reduce systolic blood pressure without a substantial reduction in diastolic blood pres- sure in patients with chronic AR.1,2,5 8 2. In symptomatic patients who are candidates for surgery, medical therapy is not a substitute for AVR. However, medical therapy is help- ful for alleviating symptoms in patients who are considered to be at very high surgical risk because of concomitant comorbid medical CLINICAL STATEMENTS AND GUIDELINES 4.3.3. Timing of Intervention Recommendations for Timing of Intervention for Chronic AR Referenced studies that support the recommendations are summarized in Online Data Supplement 15 to 17. COR LOE Recommendations In symptomatic patients with severe AR (Stage D), aortic valve surgery is indicated regardless of LV systolic function.1 7 In asymptomatic patients with chronic severe AR and LV systolic dysfunction (LVEF 55%) (Stage C2), aortic valve surgery is indicated if no other cause for systolic dysfunction is In patients with severe AR (Stage C or D) who are undergoing cardiac surgery for other indications, aortic valve surgery is indicated. In asymptomatic patients with severe AR and normal LV systolic function (LVEF >55%), aortic valve surgery is reasonable when the LV is severely enlarged (LVESD >50 mm or indexed ) (Stage C2).10,11,13 24 In patients with moderate AR (Stage B) who are undergoing cardiac or aortic surgery for other indications, aortic valve surgery is reasonable. In asymptomatic patients with severe AR and normal LV systolic function at rest (LVEF >55%; Stage C1) and low surgical risk, aortic valve surgery may be considered when there is a progressive decline in LVEF on at least 3 serial studies to the low normal range (LVEF 55% to 60%) or a progressive increase in LV dilation into the severe range (LV end- diastolic dimension [LVEDD] 3: Harm B-NR In patients with isolated severe AR who have indications for SAVR and are candidates for surgery, TAVI should not be performed.29 32 Synopsis Most patients with indications for surgery for chronic severe AR require valve replacement with a mechani- cal or bioprosthetic valve (Figure 4). Preservation of the native aortic valve ( valve sparing ) may be pos- sible in selected patients with favorable valve anatomy who are undergoing surgical replacement of the aortic sinuses and/or ascending aorta.33 39 Although advanc- es are occurring in primary aortic valve repair,37,40 42 this approach is not yet generalizable, and durabil- ity is not known. Current recommendations for AVR related to severity of LV dilation are based on mea- surement of LV short-axis diameters. There are limited data demonstrating prognostic value of LV volume measurements in chronic AR using left ventriculogra- Normal limits for LV volumes have been determined, as have criteria for severe LV dilation, but these values differ between 2D echocardiography, 3D echocardiography, and there are insufficient data on the relationship between LV volumes and outcomes of patients with AR. This is an area in need of further investigation. Other markers of LV dysfunction and re- modeling, such as global longitudinal strain and circu- likewise require additional clinical outcome studies. Recommendation-Specific Supportive Text 1. Symptoms are an important indication for AVR in patients with chronic severe AR, and the most important aspect of the clinical evaluation is tak- ing a careful, detailed history to elicit symptoms or diminution of exercise capacity. Patients with chronic severe AR who develop symptoms have a high risk of death if AVR is not performed,52 and survival and functional status after AVR are related to the severity of preoperative symptoms, assessed either subjectively or objectively with Even among symptomatic patients with a severe reduction in LVEF (<35%), AVR results in improved survival rate.5 7 2. LV systolic function is an important determi- nant of survival and functional status after Outcomes are optimal when surgery is performed before LVEF decreases In asymptomatic patients with LV systolic dysfunction, postoperative out- comes are better if AVR is performed before onset of symptoms.53 3. Patients with chronic severe AR may be referred for other types of cardiac surgery, such as CABG, mitral valve surgery, or surgery for correction of dilation of the aortic root or ascending aorta. In these patients, AVR will prevent both the hemo- dynamic consequences of persistent AR during the perioperative period and the possible need for a second cardiac operation in the near future. Patients undergoing surgical repair or replacement of the aortic root or ascending aorta may be can- didates for aortic valve sparing procedures.33 39 4. LVESD in patients with chronic AR reflects both the severity of the LV volume overload and the degree of LV systolic shortening.54,62 An elevated LVESD often reflects LV systolic dysfunction with a depressed LVEF. If LVEF is normal, an increased LVESD indicates a significant degree of LV remod- eling and is associated with subsequent develop- ment of symptoms and/or LV systolic dysfunction and an increased mortality rate after AVR.17,20,21 Most studies have used unadjusted LVESD, but indexing for body size is important, particularly in women or small patients.13,19,52 Recent data indi- cate that the LVESD index threshold for optimal postoperative survival may be even smaller than but more outcome data, and ide- ally an RCT, of earlier intervention are needed. CLINICAL STATEMENTS AND GUIDELINES LV volumes may be a more sensitive predictor of cardiac events than LVESD index in asymptomatic but more data are needed to deter- mine the threshold values of LV systolic volume that best predict postoperative outcomes. 5. In patients with moderate AR who are undergo- ing other forms of cardiac surgery, such as CABG, mitral valve surgery, or replacement of the ascend- ing aorta, the decision to intervene on the aortic valve concurrently includes consideration of several factors, including aortic valve anatomy, aortic root size and shape, regurgitant severity, other comor- bidities, and patients preferences and values. Patients undergoing surgical repair or replacement of the aortic root or ascending aorta may be candi- dates for a valve-sparing procedure.33 39 6. LVEDD, a marker of the severity of LV volume overload in patients with chronic AR, is signifi- cantly associated with clinical outcomes in asymp- tomatic patients, and progressive increases in LVEDD are associated with subsequent need for In asymptomatic patients, it is important to ensure that apparent changes in LV size or LVEF are not due simply to measurement or physiological variability. In addition, confirmation of severe regurgitation by quantitative measures of AR severity with TTE, TEE, or, when needed, CMR provides confidence that AR is the cause of LV dila- tion or decrease in LVEF. When there is an apparent significant fall in EF or increase in LV size, repeat imaging typically is performed at 3- to 6-month intervals unless there is clinical deterioration. 7. TAVI for isolated chronic AR is challenging because of dilation of the aortic annulus and aortic root and, in many patients, lack of sufficient leaflet calcification. Risks of TAVI for treatment of AR include transcatheter valve migration and signifi- cant paravalvular leak.29 32 TAVI is rarely feasible, and then only in carefully selected patients with severe AR and HF who have a prohibitive surgi- cal risk and in whom valvular calcification and annular size are appropriate for a transcatheter approach. Figure 4. Timing of intervention for AR. Colors correspond to Table 2. AR indicates aortic regurgitation; AVR, aortic valve replacement; EDD, end-diastolic dimension; ERO, effective regurgi- tant orifice; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; RF, regurgitant fraction; RVol, regurgitant volume; and VC, vena contracta CLINICAL STATEMENTS AND GUIDELINES 5. BICUSPID AORTIC VALVE 5.1. BAV and Associated Aortopathy 5.1.1. Diagnosis and Follow-Up of BAV 5.1.1.1. Diagnostic Testing: Initial Diagnosis Recommendations for Diagnostic Testing: Initial Diagnosis of BAV Referenced studies that support the recommendations are summarized in Online Data Supplement 18. COR LOE Recommendations In patients with a known BAV, TTE is indicated to evaluate valve morphology, measure severity of AS and AR, assess the shape and diameter of the aortic sinuses and ascending aorta, and evaluate for the presence of aortic coarctation for prediction of clinical outcome and to determine timing In patients with BAV, CMR angiography or CT angiography is indicated when morphology of the aortic sinuses, sinotubular junction, or ascending aorta cannot be assessed accurately or fully by echocardiography.4,5 In first-degree relatives of patients with a known BAV, a screening TTE might be considered to look for the presence of a BAV or asymptomatic dilation of the aortic sinuses and ascending aorta.6 Synopsis BAV is a common congenital anomaly that affects 0.5% to 2.0% of adults with a 3:1 male-to-female predomi- Patients with BAV may develop isolated aortic valve disease, including isolated AR, AS, or a combina- tion of the two. Aortic aneurysms have been reported in 20% to 40% of patients with BAV.1 This aortopathy can occur independent of valve function and consists of dilation of the aortic sinuses, the ascending aorta, or the arch. Therefore, patients with BAV require care- ful evaluation of both the aortic valve and the aorta throughout their lifetimes (Figure 5). Recommendation-Specific Supportive Text 1. Many patients with BAV will develop AS or AR over their lifetimes. In a recent meta-analysis of natural history studies of patients with BAV, 13% to 30% of patients developed moderate or greater AR and 12% to 37% developed moderate or greater AS during follow-up.1 TTE usually is adequate for evaluation of aortic valve anatomy and hemody- namics. TEE provides improved 2D and 3D images if needed. Aortic enlargement at the level of the sinuses or proximal ascending aorta has been reported in 20% to 40% of patients with BAV,1 and some develop severe aneurysmal dilation and are at increased risk of aortic dissection.2,3,7 10 Aortic measurements are reported at the aortic annulus, sinuses of Valsalva, sinotubular junction, and mid-ascending aorta. Doppler interrogation of the proximal descending aorta and abdominal aorta should also be performed to evaluate for the presence of aortic coarctation, which is asso- ciated with BAV in a subset of patients, although a coarctation also can be detected by comparing arm and leg blood pressures. 2. CT angiography or CMR provides better images of the aortic sinuses, sinotubular junction, or ascending aorta when TTE does not adequately visualize the sinus and proximal 5 to 6 cm of the ascending aorta. The choice of CMR versus CT angiography depends on patient preference, insurance coverage, institutional expertise, and consideration of radiation exposure. 3. In about 20% to 30% of patients with a BAV, other family members also have a BAV and/or an associated aortopathy. A specific genetic cause has not been identified, and the patterns of inheritance are variable. Imaging can identify the presence of a BAV and aortic dilation, but there is a paucity of data on the cost-effectiveness of this approach and whether earlier diagnosis would improve long-term clinical outcomes.6,11 5.1.1.2. Diagnostic Testing: Routine Follow-Up Recommendations for Diagnostic Testing: Routine Follow-Up of Patients With a BAV Referenced studies that support the recommendations are summarized in Online Data Supplement 18. COR LOE Recommendations In patients with BAV and a diameter of the aortic sinuses or ascending aorta of 4.0 cm, lifelong serial evaluation of the size and morphology of the aortic sinuses and ascending aorta by echocardiography, CMR, or CT angiography is reasonable, with the examination interval determined by the degree and rate of progression of aortic dilation and by family history.1 5 In patients with a BAV who have undergone AVR, continued lifelong serial interval imaging of the aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is 4.0 Synopsis Patients with BAV with and without associated aortic aortopathy require lifelong surveillance. Because pro- gression of valve disease and growth of the aorta can occur in the absence of symptoms, diagnostic imaging plays an integral role in the surveillance process. Recommendation-Specific Supportive Text 1. Aortopathy is present in approximately 20% to 40% of patients with a BAV and is associated with dilation of the aortic sinuses, the ascending aorta, and/or the arch.1 In a retrospective case series of 918 patients with BAV followed for 2 to 12 years CLINICAL STATEMENTS AND GUIDELINES with serial imaging, 47% required valve surgery but only 3.8% required aortic grafting without valve replacement, and <0.1% had aortic dissec- In a systematic review of 13 studies with >11000 patients with a BAV, aortic dilation was present in 20% to 40%, but only 0.4% suffered Aortic imaging at least annually is prudent in patients with BAV and significant aor- tic dilation (>4.5 cm) to determine the appropriate timing of surgical intervention. Patients with risk factors that increase the risk of aortic dissection, such as a rapid rate of change in aortic diameter or a family history of aortic dissection, may also require more frequent monitoring. In patients with milder dilation that shows no change on sequential studies and with a negative family his- tory, a longer interval between imaging studies is 2. In a retrospective review of 1286 patients with a BAV who underwent isolated AVR with a median of 12 years of follow-up, subsequent aortic dissection occurred in 1%, ascending aor- tic replacement surgery was needed in 0.9%, and progressive aortic enlargement was noted in In a smaller cohort of 153 patients with a BAV with prior AVR, 3% required proximal aor- tic surgery after 15 years of follow-up. No cases of aortic dissection were noted.7,10 These stud- ies demonstrate that the aorta may continue to dilate in patients with a BAV who undergo valve 5.1.2. Interventions for Patients With BAV 5.1.2.1. Intervention: Replacement of the Aorta Recommendations for Intervention: Replacement of the Aorta in Patients With a BAV Referenced studies that support the recommendations are summarized in Online Data Supplement 18. COR LOE Recommendations In asymptomatic or symptomatic patients with a BAV and a diameter of the aortic sinuses or ascending aorta >5.5 cm, operative intervention to replace the aortic sinuses and/ or the ascending aorta is recommended.1 3 In asymptomatic patients with a BAV, a diameter of the aortic sinuses or ascending aorta of 5.0 to 5.5 cm, and an additional risk factor for dissection (eg, family history of aortic dissection, aortic growth rate >0.5 cm per year, aortic coarctation), operative intervention to replace the aortic sinuses and/or the ascending aorta is reasonable if the surgery is performed at a Comprehensive Valve Center.3,4 Figure 5. Intervals for imaging the aorta in patients with a BAV. Colors correspond to Table 2. BAV indicates bicuspid aortic valve; CTA, computed tomographic angiography; CMR, cardiac magnetic resonance; TTE, transthoracic echocardiography. CLINICAL STATEMENTS AND GUIDELINES In patients with a BAV with indications for SAVR and a diameter of the aortic sinuses or ascending aorta 4.5 cm, replacement of the aortic sinuses and/or ascending aorta is reasonable if the surgery is performed at a Comprehensive Valve Center.4 7 In patients with a BAV who meet criteria for replacement of the aortic sinuses, valve-sparing surgery may be considered if the surgery is performed at a Comprehensive Valve Center.8,9 In asymptomatic patients with a BAV who are at low surgical risk, have a diameter of the aortic sinuses or ascending aorta of 5.0 to 5.5 cm, and have no additional risk factors for dissection, operative intervention to replace the aortic sinuses and/or the ascending aorta may be considered if the surgery is performed at a Comprehensive Valve Center.4 7,10 14 Synopsis The timing and type of surgery for replacement of the aorta are dependent on the anatomy of the aorta (as demonstrated on imaging), patient characteristics, and institutional expertise (Figure 6). Recommendation-Specific Supportive Text 1. Retrospective studies of patients with a BAV have shown that the incidence of aortic dissection is very low and is estimated to be approximately 0.4% with routine surveillance of the aorta.1 However, data are limited with regard to the degree of aortic dilation at which the risk of dissection is high enough to war- rant operative intervention in patients who do not fulfill criteria for AVR on the basis of severe AS or AR. Thus, an individualized approach to the timing of surgical intervention for a dilated aorta is suggested. Surgery is recommended in patients with a BAV with or without symptoms and with a diameter of the aortic sinuses or the ascending aorta of 5.5 cm.2 2. Specific risk factors, including family history of aortic dissection, aortic growth rate >0.5 cm per year, and aortic coarctation, are associated with a greater risk of aortic dissection. In patients with these risk factors, operative intervention to replace the aortic sinuses and/or the ascending aorta is reasonable when the aortic dimension is 5.0 to 5.5 cm, if the surgery is performed at a Comprehensive Valve Center.4,10 12,15 3. In patients with a BAV, data are limited with regard to the degree of aortic dilation at which the risk of dissection is high enough to warrant replacement of the ascending aorta at the time of AVR. The risk of progressive aortic dilation and dissection after AVR in patients with BAV has been the subject of several studies, but definitive data are lacking. In patients undergoing AVR because of severe AS or AR, replacement of the ascending aorta is reason- able when the aortic diameter is >4.5 cm.4 7,10 14 4. There are a limited number of patients with BAV who meet criteria for operative intervention on the aortic sinuses and/or ascending aorta but have a well-functioning aortic valve. Because of the growing experience with valve-sparing surgery on highly selected patients,8,9 surgical replacement of the aorta with aortic valve repair or reimplantation may be considered. However, given the complexity of this procedure, surgery should be performed at a Comprehensive Valve Center. 5. Data are limited with regard to the degree of aortic dilation at which the risk of dissection is high enough to warrant operative intervention in patients who do not fulfill criteria for AVR on the basis of severe AS or AR. In asymptomatic patients with a BAV and a diameter of the aortic sinuses and/or ascending aorta of 5.0 to 5.5 cm who are at low surgical risk and have no additional risk factors for aortic dissection, surgery to replace the aortic sinuses and/or ascending aorta may be considered as long as surgery is performed at a Comprehensive Valve Center. Additionally, shared decision-making between the patient and the healthcare team is needed to clearly outline the risks of surgery and weigh them against the potential reduction in future risk of aortic dissection.4 7,10 14 5.1.2.2. Intervention: Repair or Replacement of the Aortic Valve Recommendations for Intervention: Repair or Replacement of the Aortic Valve Referenced studies that support the recommendations are summarized in Online Data Supplement 18. COR LOE Recommendations In patients with BAV and severe AR who meet criteria for AVR, aortic valve repair may be considered in selected patients if the surgery is performed at a Comprehensive Valve Center.1 3 In patients with BAV and symptomatic, severe AS, TAVI may be considered as an alternative to SAVR after consideration of patient- specific procedural risks, values, trade-offs, and preferences, and when the surgery is performed at a Comprehensive Valve Center.4 6 Synopsis The indications for the timing of aortic valve interven- tion in patients with a BAV and AS or AR is similar to those for trileaflet aortic valves. See the respective sec- tions on AS (Section 3.2) and AR (Section 4). The choice of prosthetic valve type in patients with a BAV is similar to that for patients with trileaflet valves. See the sec- tion on prosthetic valve choices (Section 3.2.4.1) for full details. Given the unique nature of BAV, however, there are additional specific considerations. Recommendations for Intervention: Replacement of the Aorta in Patients With a BAV (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. Surgical repair of the aortic valve may be feasible in selected patients, depending on valve and aortic root anatomy and tissue characteristics. Published data suggest that valve repair can be performed safely and effectively by surgeons with training and experience in these techniques.1 3,7 However, given the complexities of patient selection and surgical techniques, such surgeries should be per- formed at a Comprehensive Valve Center. 2. Recent trials have demonstrated the benefits of TAVI in patients with severe, symptomatic AS. However, the early pivotal TAVI trials excluded patients with BAV. Initial studies using early-gener- ation valves suggested a higher rate of paravalvular leak in the BAV population.4,5 Data from the STS/ ACC Transcatheter Valve Therapies Registry, which includes all consecutive TAVI procedures performed in the United States, suggest that with the use of newer-generation prosthetic valves the rate of paravalvular leak is no different in patients with a BAV than in patients with a trileaflet aortic valve. This registry also showed no difference in mortality rate at 30 days and 1 year between the BAV and tricuspid valve groups. However, the stroke rate at 30 days was higher in the BAV group.6 Other con- siderations are the younger age of patients with a BAV, for whom the risk benefit ratio of TAVI versus SAVR needs careful consideration. RCTs are needed to obtain full clarity on the optimal use of TAVI in this population, as well as long-term outcomes. 6. MITRAL STENOSIS The incidence of rheumatic MS is low in high-income countries and has been slowly declining in low- and mid- dle-income countries, but MS remains a major cause of valve disease worldwide. Rheumatic MS is much more common in women (about 80% of cases) than in men. The clinical presentation of rheumatic MS varies, with patients from regions with a high disease prevalence presenting at a young age (teen years to age 30 years) Figure 6. Intervention for replacement of the aorta in patients with a BAV. Colors correspond to Table 2. *Family history of aortic dissection, aortic growth rate 0.5 cm/y, and/or presence of aortic coarctation. BAV indicates bicuspid aortic valve; AVR, aortic valve re- placement; and CVC, Comprehensive Valve Center. CLINICAL STATEMENTS AND GUIDELINES with commissural fusion but pliable noncalcified valve leaflets. In contrast, the presentation in regions with a low disease prevalence occurs more often in older pa- tients (age 50 to 70 years) who present decades after the initial rheumatic fever episode with calcified fibrotic leaf- lets in addition to commissural fusion and subvalvular involvement. Older patients with MS often have multiple other cardiac and noncardiac comorbidities, such as ath- erosclerotic disease, hypertension, and diastolic dysfunc- tion, all of which need to be taken into consideration in patient evaluation and management.1,2 Although most of MS in the world results from rheumat- ic heart disease, nonrheumatic calcific MS is found with in- creasing frequency in the elderly population in high-income countries Calcific MS is the result of calcification of the mi- tral annulus that extends into the leaflet bases, resulting in both narrowing of the annulus and rigidity of the leaflets.3 5 6.1. Stages of MS The stages of MS are defined by patient symptoms, valve anatomy, valve hemodynamics, and the consequences of valve obstruction on the left atrium (LA) and pulmo- nary circulation (Table 16). Rheumatic valve disease is the primary cause of MS, with anatomic features reflect- ing this disease process. Hemodynamic severity is best characterized by valve area, either directly planimetered by 2D or 3D imaging or calculated from the diastolic The definition of severe MS is based on the severity of symptoms, as well as the sever- ity at which intervention will improve symptoms. Thus, a mitral valve area 1.5 cm2 is considered severe, which typically corresponds to a transmitral mean gradient of >5 mmHg to 10 mmHg at a normal heart rate. How- ever, mean pressure gradient is highly dependent on transvalvular flow rate, the diastolic filling period, and heart rate. Mitral pressure half-time also has limitations, and is dependent upon LV and LA compliance as well as stenosis severity. Other approaches to calculation of the mitral valve area, such as the continuity equation or Gorlin formula, may be used if discrepancies exist. These pertain primarily to patients with rheumatic MS. 6.2. Rheumatic MS 6.2.1. Diagnosis and Follow-Up of Rheumatic MS 6.2.1.1. Diagnostic Testing: Initial Diagnosis Recommendations for Diagnostic Testing: Initial Diagnosis of Rheumatic MS Referenced studies that support the recommendations are summarized in Online Data Supplement 19. COR LOE Recommendations In patients with signs or symptoms of rheumatic MS, TTE is indicated to establish the diagnosis, quantify hemodynamic severity, assess concomitant valvular lesions, and demonstrate valve morphology (to determine suitability for mitral commissurotomy).1 3 In patients considered for percutaneous mitral balloon commissurotomy (PMBC), TEE should be performed to assess the presence or absence of LA thrombus and to evaluate the severity of MR.4 6 Synopsis For patients with rheumatic MS, TTE is the initial di- agnostic test to determine the severity of the stenosis Table 16. Stages of MS Stage Definition Valve Anatomy Valve Hemodynamics Hemodynamic Consequences Symptoms A At risk of MS Mild valve doming during diastole Normal transmitral flow velocity None None B Progressive MS Rheumatic valve changes with commissural fusion and diastolic doming of the mitral valve leaflets Planimetered mitral valve area Increased transmitral flow velocities Mitral valve area >1.5 cm2 Diastolic pressure half-time Mild to moderate LA enlargement Normal pulmonary pressure at rest None C Asymptomatic severe MS Rheumatic valve changes with commissural fusion and diastolic doming of the mitral valve leaflets Planimetered mitral valve area Mitral valve area 1.5 cm2 Diastolic pressure half-time Severe LA enlargement Elevated PASP >50 mm Hg None D Symptomatic severe MS Rheumatic valve changes with commissural fusion and diastolic doming of the mitral valve leaflets Planimetered mitral valve area Mitral valve area 1.5 cm2 Diastolic pressure half-time Severe LA enlargement Elevated PASP >50 mm Hg Decreased exercise tolerance Exertional dyspnea The transmitral mean pressure gradient should be obtained to further determine the hemodynamic effect of the MS and is usually >5 mm Hg to 10 mm Hg in severe MS; however, because of the variability of the mean pressure gradient with heart rate and forward flow, it has not been included in the criteria for severity. LA indicates left atrial; MS, mitral stenosis; and PASP, pulmonary artery systolic pressure. CLINICAL STATEMENTS AND GUIDELINES and suitability for PMBC. If PMBC is being considered, a TEE can further evaluate the presence and severity of concomitant MR and rule out LA thrombus. Recommendation-Specific Supportive Text 1. TTE is the imaging modality of choice to eluci- date the anatomy and functional significance of rheumatic MS.1 The parasternal long-axis window can identify the characteristic diastolic doming of the mitral valve, whereas short-axis scanning will demonstrate commissural fusion and allow planimetry of the mitral orifice. Use of 3D echocardiography (either TTE or TEE) pro- vides greater accuracy of measurement of the mitral valve area.7,8 Doppler echocardiography mean transvalvular gradients always should be reported with heart rate because a high heart rate will result in overestimation of stenosis severity.9 Estimated RV systolic pressure is obtained from the TR velocity. Concomitant MR should be quan- tified, along with any other valve lesions (Section 7.3.1.1). Several scores are available for evalua- tion of mitral valve morphology and prediction of outcomes with PMBC, and these scores consider valve thickening, mobility, and calcification with subvalvular chordal fusion.10,11 Characterization of commissural morphology and calcification fur- ther predicts suitability for commissurotomy.2,3,12,13 Additional assessment of rheumatic MS includes the mitral pressure half-time, with acknowledg- ment that this parameter is also affected by LA and LV compliance. If the mean gradient does not match the valve area, other methods, such as the continuity equation, should be considered.14 2. TEE offers excellent visualization of the mitral valve and LA and is an alternative approach to assessment of rheumatic MS in patients whose TTE images are technically limited. In patients being considered for PMBC, a TEE can rule out LA cavity and appendage thrombi.4 6 TEE also is use- ful for evaluation of MR severity in patients being considered for PMBC because shadowing of the LA on TTE may result in underestimation of MR severity. MR that is more than mild is a contrain- dication to PMBC. 6.2.1.2. Diagnostic Testing: Changing Signs or Symptoms Patients with an established diagnosis of rheumatic MS may experience a change in symptoms attributable to disease progression related to recurrent episodes of rheu- matic fever leading to further valve damage; progressive narrowing of the mitral valve attributable to leaflet fibro- sis and thickening; progressive pulmonary hypertension; or worsening of concomitant MR or other valve lesions. In addition, symptom status may change with no change in rheumatic MS severity because of an increased he- modynamic load (for example, because of pregnancy), new-onset or rapid AF, fever, anemia, or hyperthyroid- ism, or hemodynamic shifts in the perioperative period of patients undergoing noncardiac surgery. In such cases, a repeat TTE examination can quantify the mitral valve gradient and area, as well as other parameters that may contribute to a change in symptoms. 6.2.1.3. Diagnostic Testing: Routine Follow-Up Rheumatic MS is a slowly progressive disease, char- acterized by a prolonged latent phase between the initial rheumatic illness and the development of valve The latent phase is an interval typically measured in decades in high-income countries but in considerably shorter periods in low- to middle-in- come countries, likely because of recurrent carditis. Once mild stenosis has developed, further narrow- ing is slow (decrease in valve area of 0.1 cm2 per year on average), although the rate of progression is highly variable.3 Importantly, progressive enlarge- ment of the RV and a rise in RV systolic pressure can be observed, even in the absence of a decrease in mitral valve area. Accordingly, repeat TTE at intervals dictated by valve area is an important aspect of dis- ease management, even in patients without symp- toms (Table 4). 6.2.1.4. Diagnostic Testing: Cardiac Catheterization In the contemporary era, assessment of MS and associ- ated lesions can be obtained in most patients by TTE, occasionally supplemented by TEE. However, there will be a subset of patients with nondiagnostic studies or for whom there is discordance between the clinical and echocardiographic findings. In older patients, other fac- tors contributing to symptoms may need to be further sorted out, such as concomitant diastolic dysfunction, LA noncompliance, or intrinsic pulmonary vascular dis- ease. Cardiac catheterization is useful in these patients to further characterize rheumatic MS hemodynamics and etiology of symptoms, as it can measure absolute pressures in the LV, LA, and pulmonary circulation at rest and with exercise. Although the mean pulmonary artery wedge pressure is an acceptable substitute for mean LA pressure, the LV to pulmonary wedge gra- dient will overestimate the true transmitral gradient because of phase delay and delayed transmission of Nonetheless, the absolute mean pulmonary artery wedge pressure and its relationship to the LV diastolic pressure and pulmonary artery pres- sure can provide useful clinical information. The Gorlin equation can be used for an independent calculation of mitral valve area.2,3 CLINICAL STATEMENTS AND GUIDELINES 6.2.1.5. Diagnostic Testing: Exercise Testing Recommendation for Diagnostic Testing: Exercise Testing in Patients With Rheumatic MS COR LOE Recommendation In patients with rheumatic MS and a discrepancy between resting echocardiographic findings and clinical symptoms, exercise testing with Doppler or invasive hemodynamic assessment is recommended to evaluate symptomatic response, exercise capacity, and the response of the mean mitral gradient and pulmonary artery pressure.1 5 Synopsis Exercise testing with either Doppler echocardiography or cardiac catheterization is important when the resting hemodynamics do not match the clinical symptoms in patients with rheumatic MS. Recommendation-Specific Supportive Text 1. Exercise testing with hemodynamics is helpful in the management of rheumatic MS when a patient s symptoms seem significantly greater than or less than would be expected from TTE. Results have been published in which both exercise and dobu- tamine were used with Doppler echocardiography, although exercise is preferred in general as the more Most experience is with tread- mill exercise, with images and Doppler obtained immediately after stress, but bicycle exercise allows data acquisition at various stages of exercise. Bicycle exercise testing during cardiac catheterization can also be performed for direct measurements of pul- monary artery wedge pressure and pulmonary pres- sures at rest and with exercise. Simple functional capacity helps to quantify the patient s symptoms. Changes in valve gradient should be measured, as well as the estimated pulmonary artery systolic pressure. If the patient cannot exercise, increasing the heart rate with maneuvers such as leg lifts or sit-ups may be useful. 6.2.2. Medical Therapy Recommendations for Medical Therapy in Patients With Rheumatic MS Referenced studies that support the recommendations are summarized in Online Data Supplement 20. COR LOE Recommendations In patients with rheumatic MS and 1) AF, 2) a prior embolic event, or 3) an LA thrombus, anticoagulation with a VKA is indicated.1 7 In patients with rheumatic MS and AF with a rapid ventricular response, heart rate control can be beneficial.8 In patients with rheumatic MS in normal sinus rhythm with symptomatic resting or exertional sinus tachycardia, heart rate control can be beneficial to manage symptoms.9 15 Synopsis In patients with rheumatic MS and AF, anticoagulation decreases the incidence of thromboembolic events. An- ticoagulation can also decrease the incidence of throm- boembolic events in patients with rheumatic MS if there has been a prior embolic event or if an LA throm- bus was visualized. In symptomatic patients with MS who are in normal sinus rhythm and have tachycardia, heart rate control with beta blockers, calcium channel blockers, or ivabradine will lengthen the diastolic fill- ing period and lower LA pressure. However, routine use of heart rate control for patients with rheumatic MS in normal sinus rhythm in the absence of tachycardia may result in chronotropic incompetence, preventing an ad- equate cardiac output response to exercise. Recommendation-Specific Supportive Text 1. Patients with rheumatic MS with AF and prior embolic events are at high risk of arterial embo- lization when AF or an LA thrombus is present. Treatment with VKA anticoagulation will decrease the incidence of these events.3 7,16 It is controver- sial whether long-term anticoagulation should be given to patients with rheumatic MS in normal sinus rhythm on the basis of LA enlargement or spontaneous contrast on TEE.17,18 Patients with very large left atria have more spontaneous echo- cardiographic contrast and lower LA appendage which have been associated with a higher rate of embolic events, but no data directly link large left atria to embolic events. Non vitamin K oral anticoagulation has not been studied in patients with rheumatic MS, and these patients were excluded from the randomized AF trials. In addition to the much higher risk of embo- lization with rheumatic valve disease as compared with other causes of valve disease, there is con- cern that rheumatic disease also affects the atrial muscle, resulting in an increased risk of blood flow stasis and thrombosis in the body of the LA, as well as the LA appendage.1 Further studies are required to confirm these findings.2 2. Patients with rheumatic MS are prone to develop- ing atrial arrhythmias specifically AF. Significant detrimental hemodynamic consequences may be associated with the acute development of AF, pri- marily from the rapid ventricular response, which shortens the diastolic filling period and increases The treatment of acute AF consists of anticoagulation and control of the heart rate response with negative dromotropic agents. If the rate cannot be adequately controlled with medica- tions, cardioversion may be necessary to improve hemodynamics. In the stable patient, the decision CLINICAL STATEMENTS AND GUIDELINES for rate control versus rhythm control is dependent on multiple factors, including the duration of AF, hemodynamic response to AF, LA size, prior epi- sodes of AF, and history of embolic events. It is more difficult to achieve rhythm control in patients with rheumatic MS because the rheumatic process itself may lead to progressive fibrosis and enlargement of the atria, fibrosis of the internodal and interatrial tracts, and damage to the sinoatrial node. 3. The use of negative dromotropic agents for the treatment of symptoms in patients with rheumatic MS in normal sinus rhythm has been controversial. Although a reduction in heart rate and prolonga- tion of the diastolic filling period will decrease the transmitral mean gradient, studies have shown that treatment with beta blockade may not improve or may even decrease exercise tolerance, most likely because of the limitation of the cardiac output attributable to a limited stroke volume and Nonetheless, there are now several randomized trials that have exam- ined beta blockers and ivabradine in patients with rheumatic MS and have shown that either drug can increase exercise duration and improve symp- To explain these differences, the earlier trials that found no benefit of beta blockers were performed in older patients with underlying chro- notropic incompetence, whereas the randomized trials showing benefit were performed primarily in younger patients with higher resting and exercise- induced heart rates. Thus, the use of beta blockers or ivabradine to improve symptoms may be effec- tive only in patients who do not have underlying chronotropic incompetence. When medical ther- apy is considered for relief of symptoms in patients with rheumatic MS, it must be remembered that intervention with PMBC relieves symptoms in those patients with an appropriate valve morphology. Recommendations for Intervention for Rheumatic MS Referenced studies that support the recommendations are summarized in Online Data Supplements 21 to 24. COR LOE Recommendations In symptomatic patients (NYHA class II, III, or IV) with severe rheumatic MS (mitral valve , Stage D) and favorable valve morphology with less than moderate (2+) MR* in the absence of LA thrombus, PMBC is recommended if it can be performed at a Comprehensive Valve Center.1 12 In severely symptomatic patients (NYHA class III or IV) with severe rheumatic MS (mitral , Stage D) who 1) are not candidates for PMBC, 2) have failed a previous PMBC, 3) require other cardiac procedures, or 4) do not have access to PMBC, mitral valve surgery (repair, commissurotomy, or valve replacement) is indicated.6,7,13 In asymptomatic patients with severe rheumatic MS (mitral valve area 1.5 cm2 , Stage C) and favorable valve morphology with less than 2+ MR in the absence of LA thrombus who have elevated pulmonary pressures (pulmonary artery systolic pressure >50 mmHg), PMBC is reasonable if it can be performed at a Comprehensive Valve Center.14 In asymptomatic patients with severe rheumatic MS (mitral valve area 1.5 cm2 , Stage C) and favorable valve morphology with less than 2+/ MR* in the absence of LA thrombus who have new onset of AF, PMBC may be considered if it can be performed at a Comprehensive Valve Center.15 In symptomatic patients (NYHA class II, III, or IV) with rheumatic MS and an mitral , if there is evidence of hemodynamically significant rheumatic MS on the basis of a pulmonary artery wedge pressure >25 mmHg or a mean mitral valve gradient >15 mmHg during exercise, PMBC may be considered if it can be performed at a Comprehensive Valve Center.16 In severely symptomatic patients (NYHA class III or IV) with severe rheumatic MS (mitral valve , Stage D) who have a suboptimal valve anatomy and who are not candidates for surgery or are at high risk for surgery, PMBC may be considered if it can be performed at a Comprehensive Valve Center.17 19 *2+ on a 0 to 4+ scale according to Sellar s criteria or less than moderate by Doppler echocardiography.20 Synopsis The optimal treatment of patients with rheumatic MS is either PMBC or surgery (open or closed commissuroto- my). Although these procedures can result in excellent outcomes by splitting open fused commissures to re- lieve stenosis, both the catheter-based and the surgical procedures require a high level of expertise and should be performed at experienced centers. In the United States, there has been a 7.5% decrease in the use of PMBC, accompanied by a 15.9% increase in complica- Excellent short- and long-term outcomes can be achieved with surgical commissurotomy, but surgical commissurotomy is not routinely or widely performed by most surgeons in the United States. Thus, in the clini- cal decision-making process for a patient with rheumat- ic MS, it is essential to know the results of the available interventional procedures. Mitral valve replacement is an option for treatment only if there is no other option and the patient has severe limiting symptoms (Figure 7). Recommendation-Specific Supportive Text 1. Randomized trials have established the safety and efficacy of PMBC as compared with surgical closed or open commissurotomy in patients with a Recommendations for Intervention for Rheumatic MS (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES favorable valve morphology with less than 2+ MR in the absence of LA thrombus.6,8 12 PMBC is per- formed by advancing one or more balloon cath- eters across the mitral valve and inflating them, thereby splitting the commissures. Favorable valve morphology consists of mobile and relatively thin valve leaflets, which are free of calcium, in the absence of significant subvalvular fusion.18,19,22,23 An anatomic mitral morphology score can be used to determine suitability for PMBC and to evaluate the appearance of the commissures and degree of calcification.1,24,25 Clinical factors, such as age, NYHA class, and presence or absence of AF, are also predictive of outcome. Older patients with lower gradients (<10 mmHg) will not have as good an outcome as patients with higher gra- dients, probably because of other concomitant problems that cause symptoms, such as LV dia- stolic dysfunction and LA noncompliance, mea- sured by net atrial ventricular compliance.26 30 PMBC should be performed only by experienced operators, with immediate availability of surgical backup for potential complications. Long-term follow-up has shown 70% to 80% of patients with an initial good result after PMBC to be free of recurrent symptoms at 10 years, and 30% to 40% are free of recurrent symptoms at 20 years.1 7 2. Mitral valve surgery is an established therapy for rheumatic MS, with the preferred approach being commissurotomy (either closed, where the valve is opened blindly through the LA or LV, or open, which allows more extensive surgery under direct visual- ization) when anatomy is favorable.31 36 However, in the presence of severe valvular thickening and subvalvular fibrosis with leaflet tethering, mitral valve replacement may be the best option. In addi- tion to those who have suboptimal valve anatomy (or failed PMBC), patients with moderate or severe TR may also have a better outcome with a surgi- cal approach that includes tricuspid valve repair.37 Patients undergoing surgical commissurotomy at centers with a high level of expertise may have better long-term outcomes than those undergoing Because the natural history of rheumatic MS is one of slow progression over decades, sur- gery should be delayed until the patient has severe limiting symptoms (NYHA class III or IV), particu- larly if mitral valve repair is contemplated. asymptomatic will do well for years without inter- vention, an elevation of pulmonary artery pressure is an indication that there is progressive elevation of LA pressure affecting the pulmonary circulation. An elevated pulmonary pressure can be assessed by Doppler echocardiography. Although there may be a decrease in pulmonary pressure after relief of the rheumatic MS,38 some patients will have developed intrinsic pulmonary vascular disease, as evidenced by a poorer long-term survival rate in patients who have pulmonary hypertension before Figure 7. Intervention for MS. Colors correspond to Table 2. *Repair, commis- surotomy, or valve replacement. AF indicates atrial fibrillation; CVC, Comprehensive Valve Center; MR, mitral regurgitation; MS, mitral stenosis; MV, mitral valve; MVA, mitral valve area; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; and PMBC, percutaneous mitral balloon commissurotomy. CLINICAL STATEMENTS AND GUIDELINES An elevated pulmonary arterial resistance before intervention is associated with RV dysfunction and TR after the procedure.40 42 Thus, PMBC may prevent the adverse consequences of irreversible pulmonary hypertension if it can be performed with a high success rate and low risk in patients who are developing pulmonary hyper- tension. Correction of the MR before irreversible changes occur can be curative. Thus, in chronic primary MR, MR is the disease. 4. The new onset of AF may be an indication for pro- ceeding with PMBC in the asymptomatic patient with a favorable valve morphology for several rea- sons. First, AF may be the equivalent of symptom onset, signifying that rheumatic MS is resulting in progressive LA damage. Second, AF increases the risk of thromboembolic events in patients with rheumatic MS. In addition, a shortened diastolic filling interval with AF and a rapid ventricular response further increase LV pressure. Finally, the presence of AF is associated with worse outcomes in patients with rheumatic MS and with subop- timal results after PMBC.43 In theory, lowering a high LA pressure after PMBC might be beneficial in restoring normal sinus rhythm. Although there is no randomized trial to prove the effectiveness of intervening early, there is a documented improve- ment in P-wave dispersion after PMBC, which may affect the ability to restore normal sinus rhythm.15 5. Some patients have symptoms from rheumatic MS even with a mitral valve area >1.5 cm2 and a resting mean transmitral gradient <10 mmHg. This may be related to the variability and reliability of measuring a mitral valve area by either planim- etering a short-axis image of the mitral valve or using a diastolic half-time for indirect calculation of the mitral valve area. There are also patients who have a relatively low gradient at rest who generate a much higher gradient with exercise, with symptoms developing from the higher LA pressure. Thus, in these patients in whom there is a discrepancy between the clinical symptoms and the resting hemodynamics, exercise testing with measurement of the mean transmitral gradient or the direct pulmonary artery wedge, or both, is Patients who increase their gradients to >15 mmHg with exercise have been shown to improve symptomatically after PMBC.16 6. Both anatomic valve morphology and the pres- ence of commissural calcification predict suc- cessful PMBC. However, in all such series, this predictive ability is not absolute, with 42% of patients with an anatomic valve Wilkins morphol- ogy score >822,23,31,32 having an optimal outcome (25% increase in mitral valve area to >1.5 cm2 ) and 38% of patients with commissural calcium having event-free survival at 1.8 years.18,19,22,23 Accordingly, severely symptomatic patients who are poor surgi- cal candidates may benefit from PMBC even with suboptimal valve anatomy.17 Patients who refuse surgery may also be offered PMBC after discussion about the potential complications associated with this procedure when it is performed in patients with suboptimal valve anatomy. 6.3. Nonrheumatic Calcific MS Recommendation for Nonrheumatic Calcific MS COR LOE Recommendation In severely symptomatic patients (NYHA class III or IV) with severe MS (mitral valve area 1.5 , Stage D) attributable to extensive mitral annular calcification, valve intervention may be considered only after discussion of the high procedural risk and the individual patient s preferences and values.1 3 Synopsis Although most MS in the world results from rheumatic heart disease, calcific MS is found with increasing fre- quency in the elderly population in high-income coun- Calcific MS is the result of calcification of the mitral annulus that extends into the leaflet bases, result- ing both in narrowing of the annulus and rigidity of the leaflets. In contrast to rheumatic MS, there is no commis- sural fusion, and the leaflet tips are usually unaffected. The progression of calcific MS is variable, ranging from an increase of <1.0 to up to 9 mmHg per year.9,11 The prognosis of this group of patients is poor, with a 5-year survival rate <50%, most likely because of advanced age and other comorbidities.4 Determination of the severity of stenosis is difficult because of extensive calcification, which prevents measurement of an accurate planime- tered area, and the significant abnormalities of LA and LV compliance, which cause a high gradient in the absence of severe obstruction.12 16 These patients are at high risk with any intervention because of the extensive calcifica- tion, as well as advanced age and multiple comorbidi- ties. Thus, in patients with calcific MS, the indications for any intervention differ from those for rheumatic MS, and intervention for calcific MS should be performed only in the highly symptomatic patient. Nonrheumatic MS can also be present after radiation therapy and after a mitral valve repair with a small annuloplasty ring. Recommendation-Specific Supportive Text 1. Indications for intervention in patients with cal- cific MS are different from those for rheumatic MS for the following reasons. First, because calci- fication involves the annulus and base of the leaf- lets without commissural fusion, there is no role CLINICAL STATEMENTS AND GUIDELINES for PMBC or surgical commissurotomy. Second, the presence of severe mitral annular calcification can be quite challenging for the surgeon because of technically difficult in securely attaching the prosthetic valve and placement of the prosthetic valve may result in narrowing of the orifice.17 22 Finally, patients with calcification are often elderly and debilitated, have multiple comorbidities, and are at high surgical risk.1 3 For these reasons, intervention should be delayed until symptoms are severely limiting and cannot be managed with diuresis and heart rate control. Catheter-based therapies for these high surgical risk patients are being developed and evaluated.23 7. MITRAL REGURGITATION 7.1. Acute MR Acute MR may be caused by disruption of different parts of the mitral valve apparatus. IE may cause leaflet perfo- ration or chordal rupture. Spontaneous chordal rupture may occur in patients with myxomatous mitral valve dis- ease. Rupture of the papillary muscle occurs in patients who have an acute ST-segment elevation myocardial infarction, usually associated with an inferior infarction. The acute volume overload on the LV and LA results in pulmonary congestion and low forward cardiac out- Diagnosis of the presence and etiology of acute MR, along with urgent intervention, may be lifesaving. 7.1.1. Diagnosis of Acute MR In patients with acute MR, TTE is the initial imaging mo- dality of choice to evaluate LV function, RV function, pulmonary artery pressure, and mechanism of MR. The patient with severe acute MR, which might occur from chordal rupture, usually experiences acute hemody- namic decompensation. The sudden volume overload increases LA and pulmonary venous pressures, leading to pulmonary congestion and hypoxia, whereas de- creased blood delivery to the tissues with a concomitant decrease in LV systolic pressure limits the pressure gradi- ent, driving MR to early systole. Thus, the murmur may be short and unimpressive, as may be the color jet of MR by TTE. In the presence of sudden acute and he- modynamic instability after myocardial infarction, with hyperdynamic LV function by TTE and no other cause for the deterioration, TEE can be especially helpful in detecting papillary muscle or chordal rupture or valvular vegetations and annular abscesses that may further ac- centuate the need for a more urgent surgical approach.1 7.1.2. Medical Therapy Vasodilator therapy improves hemodynamic compen- sation in acute MR. The premise for use of vasodila- tors in acute MR is a reduction in impedance of aortic flow, thereby preferentially guiding flow away from the LV-to-LA pathway, decreasing MR while simultaneously increasing forward output to the LV-to-aortic path- This is usually accomplished by infusion of an easily titratable agent, such as sodium nitroprusside or nicardipine. Use of vasodilators is often limited by sys- temic hypotension that is exacerbated when peripheral resistance is decreased. Intra-aortic balloon counterpul- sation can be helpful to treat acute severe MR. By low- ering systolic aortic pressure, intra-aortic balloon coun- terpulsation decreases LV afterload, increasing forward output while decreasing regurgitant volume. Simulta- neously, intra-aortic balloon counterpulsation increases diastolic and mean aortic pressures, thereby supporting the systemic circulation. The use of a percutaneous cir- culatory assist device may stabilize a patient with acute hemodynamic compromise before the procedure. Prompt mitral valve surgery, preferably mitral repair if possible, is lifesaving in the symptomatic patient with acute severe primary MR. The severity of acute primary MR is variable, and some patients with more moderate amounts of MR may develop compensation as LV dila- tion allows for lower filling pressure and increased for- ward cardiac output. However, most patients with acute severe MR require surgical correction for reestablishment of normal hemodynamics and for relief of symptoms.1 5 This is especially true for a complete papillary muscle rup- ture that causes very severe MR, which is poorly tolerated. 7.2. Chronic Primary MR 7.2.1. Stages of Chronic Primary MR In assessing the patient with chronic MR, it is important to distinguish between chronic primary (degenerative) MR and chronic secondary (functional) MR, as these 2 conditions have more differences than similarities. Pri- mary MR is a disease of the mitral valve apparatus, and secondary MR is a disease of the ventricle or atria. In chronic primary MR, the pathology of 1 of the com- ponents of the valve (leaflets, chordae tendineae, papil- lary muscles, annulus) causes valve incompetence, with systolic regurgitation of blood from the LV to the LA (Table 17). The most common cause of chronic primary MR in high-income countries is mitral valve prolapse, which has a wide spectrum of etiology and presenta- tion. Younger populations present with severe myxo- matous degeneration with gross redundancy of both anterior and posterior leaflets and the chordal appa- ratus (Barlow s valve). A subset of these patients will present with ventricular arrhythmias, mitral annular disjunction, and LV dilation. Alternatively, older popu- lations present with fibroelastic deficiency disease, in which lack of connective tissue leads to chordal rup- ture. The differentiation between these 2 etiologies may have implications for operative intervention. Other CLINICAL STATEMENTS AND GUIDELINES less common causes of chronic primary MR include IE, connective tissue disorders, rheumatic heart disease, cleft mitral valve, and radiation heart disease. If vol- ume overload of chronic primary MR is prolonged and severe, it causes myocardial damage, HF, and eventual death. Correction of the MR before irreversible changes occur can be curative. 7.2.2. Diagnosis and Follow-Up of Chronic Primary MR 7.2.2.1. Diagnostic Testing: Initial Diagnosis Recommendations for Diagnostic Testing: Initial Diagnosis of Chronic MR Referenced studies that support the recommendations are summarized in Online Data Supplement 25. 