The Year in Valvular Heart Disease

Accepted Manuscript The Year in Valvular Heart Disease: 2014 Shahbudin H. Rahimtoola, MB, FRCP, D.Sc. (Hon.) PII:

S0735-1097(14)00337-4

DOI:

10.1016/j.jacc.2014.01.024

Reference:

JAC 19781

To appear in:

Journal of the American College of Cardiology

Received Date: 10 October 2013 Revised Date:

19 December 2013

Accepted Date: 7 January 2014

Please cite this article as: Rahimtoola SH, The Year in Valvular Heart Disease: 2014, Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2014.01.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT THE YEAR IN VALVULAR HEART DISEASE: 2014 Running Title: Year in Valvular Heart Disease

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Shahbudin H. Rahimtoola MB, FRCP, D.Sc. (Hon.)

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Distinguished Professor University of Southern California Griffith Professor of Cardiology Professor of Medicine Keck School of Medicine at USC Chief Physician I, LAC+USC Medical Center

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From the Griffith Center, Division of Cardiovascular Medicine, Department of Medicine, LAC+USC Medical Center, Keck School of Medicine at University of Southern California, Los Angeles, CA 90033

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DISCLOSURE: Dr.Rahimtoola has received Honoraria for educational lectures from American College of Cardiology Foundation; American College of Physicians; University of California Los Angeles; University of California Irvine; Cornell University; Creighton University; Thomas Jefferson University; Cedars-Sinai Medical Center; Harvard Medical School; University of Wisconsin; University of Hawaii; Cardiologists Association of Hong Kong, China; University of California, Fresno; University of Arizona, Tucson Medical Center; ATS; St. Jude Medical; Carbomedics; Edwards Life Sciences; Merck; Pfizer.

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FINANCIAL SUPPORT There was no financial support for this project/manuscript

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CORRESPONDENCE: S.H. Rahimtoola M.D. University of Southern California 1200 N. State Street/ Old Gen Hosp Rm 3221 Los Angeles, CA 90033 Phone: (323) 226-7264 Fax: (323) 221-4428 E-mail: [email protected] Key Words:

Aortic Stenosis, mitral stenosis, mitral regurgitation, infective endocarditis, transcatheter valve therapy, mitral valve repair, prosthetic heart valve

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This review includes articles published in July 2012-June 2013 with 2 exceptions. GUIDELINES ON VAVULAR HEART DISEASE

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1. EUROPEAN SOCIETY OF CARDIOLOGY (ESC) AND THE EUROPEAN ASSOCIATION FOR CARDIO-THORACIC SURGERY (EACTS) 1

COMMENT: A total of 46 pages and 241 references. Of the 66 recommendations, none had

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level of evidence A. There were 28 Class I recommendations with level of evidence B in 6 and C in 22. There were 31 Class IIa recommendations with level of evidence B in 1 and C in 30. There

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are 7 Class IIb recommendations; all were with level of evidence C. AORTIC STENOSIS (AS) A. MECHANISMS

1) NORTH WESTERN ADELAIDE HEALTH STUDY

This study evaluated changes over a time period of 4 years in 204 randomly

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selected subjects aged 63 ± 6 years who had aortic sclerosis (ASc) 2 They demonstrated: i) progression occurs in the majority of the normal aging population; ii) the importance of the NO

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signaling cascade in disease development; and iii) provided additional data linking angiotensin converting enzyme-inhibitor (ACE-I)/angiotensin II receptors (ARB) with the retardation of

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ASc.

2) STUDY OF AS/ASc AND AORTIC ATHERSCLEROSIS Position emission and computed tomography was performed using 18F-sodium

fluoride and 18F-fluorodeoxyglucose in 101 patients with calcific aortic valve disease from Scotland.3 They showed AS/ASc are distinctly different processes from aortic atherosclerosis and skeletal bone formation. In AS/ASc, active calcification was more pronounced and inflammation was less prominent than in aortic atherosclerosis. In AS, eNOS uncoupling is

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markedly increased and the pathophysiological processes are locally determined and regulated in the valve itself.

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COMMENT: This study complements an earlier study.4 The accompanying editorial had pointed out that both calcific aortic valve disease and aortic atherosclerosis are very common in the older population and that correlationship does not necessarily imply a cause and effect

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relationship.5

3) GENETICS ASSOCIATIONS WITH VALVULAR CALCIFICATIONS AND AORTIC

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STENOSIS.

One Single-Nucleotide Polymorphism (SNP) in the lipoprotein (a) (LPA) locus (rs 10455872) reached genome wide significance for the presence of AV calcification (odds ratio per allele, 2.05; p = 9.0 x 10-10). This finding was replicated in additional white European, African-American, and Hispanic-American cohorts.6 Genetically determined Lp (a) levels, as

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predicted by LPA genotype, were also associated with AV calcification, “supporting a causal role for Lp (a)”. The authors concluded: “We have identified a SNP in the LPA locus that is

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significantly correlated with aortic valve calcification. Our findings implicate genetic variation at the LPA locus, through elevated plasma Lp (a) levels in the development of aortic-valve

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disease.”

COMMENT: The accompanying editorial by Dorn 7 is excellent which emphasized that the frequency of LPA gene variant is 0.03. Thus 5 or 6 persons in 100 carry this risk allele while calcification of the aortic valve occurs commonly. 4) ROLE OF OSTEOGENIC PROGENITOR CELLS (OPC) IN CALCIFIC AS Blood from patients with mild-moderate AS (n = 17), severe calcific AS (n = 26) severe AS/severe coronary artery disease (CAD) (n = 33) and controls (n = 22) were examined.8

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Patients with severe AS showed higher number of endothelial progenitor cells (EPC) with osteoblastic phenotype (ONC) than in controls. Immunofluorescence showed colocalization of

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nuclear factor Kappa-B and OCN in diseased and normal valves. CD34+/OCN+ cells were abundant in the endothelial and deeper layers of calcific AS. The authors concluded EPC-CON may play a significant role in the pathogenesis and as markers of prognostication of calcific AS.

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B. ASSESSMENT OF SEVERE AS

1. CRITERIA FOR SEVERE AS: MEAN AORTIC VALVE GRADIENT (AVG) IS AORTIC VALVE AREA (AVA) ≤ 1.0 cm2 IS RELIABLE

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PROBLEMATIC;

In an “elderly” community, in Olmsted County, MN there were 360 residents who had AS diagnosed by echocardiography from 1988 to 1997.9 96 of them had severe AS (AVA < 1.0 cm2), but 67% had mean aortic valve gradient (AVG) of < 40 mm Hg and in 32%, the mean AVG was < 30 mm Hg and left ventricular ejection fraction (LVEF) was ≥ 0.50. The reasons

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for not performing AVR included low gradient in 57%, symptoms judged equivocal in 43%, comorbidities 37%, patients refused surgery in 20% and physician choice in 20%. In patients

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who did not have surgery, the survival was worse for those with AVA < 1.0 cm2 (Figure 1). AVR was ultimately performed in 131 patients, who comprised only 45% of those with AVA <

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1.0 cm2, which reduced mortality [ hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.390.94; p = 0.02] and heart failure (HR 0.29. 95% CI 0.13-0.64, p < 0.01). COMMENT: There are three problems: 1) In this age group, a large majority of patients with severe AS (AVA Index ≤ 0.6 cm2/m2) had a mean AVG < 40 mm Hg10 as in this study. One criteria of severe AS that is used is mean AVG > 40 mm Hg which is being interpreted to indicate a mean AVG ≤ 40 mm Hg is not severe AS. It is best if the criteria of > 40 mm Hg is discarded. Alternatively, it needs to be emphasized that

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mean AVG > 40 mmHg may indicate severe AS but its specificity and positive predictive value is not known. However, in a study of 636 patients mean AVG ≥ 50 mm Hg was documented to

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be specific and the positive predictive value for severe AS was ≥ 90%.11 Moreover, it is best to rely on calculated AVA; 2) Symptoms were not attributed to AS; and 3) Physician choice. C. PROGNOSIS OF SEVERE AS

PREDICTOR OF EVENT FREE SURVIVAL

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1. AORTIC VALVE AREA INDEX (AVAI) BY ECHOCARDIOGRAPHIC/DOPPLER IS A

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In consecutive 103 asymptomatic patients, age 72 ± 11 years, those with AVAI of < 0.6 cm2/m2 versus those with AVAI ≥ 0.6 cm2/m2 had 3 year event free survival of 41% vs 86% respectively, p < 0.01,12 Actuarial total mortality data was not presented. 2. ENERGY LOSS INDEX (ELI) IS ALSO A PREDICTOR OF EVENT FREE SURVIVAL BUT IS CONTROVERSIAL FOR TOTAL MORTALITY

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Data from the SEAS study of 1563 patients with AS who were initially asymptomatic showed ELI < 0.6 cm2/m2 “provided additional prognostic information to that

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derived from conventional measures of AS severity.” 13 In patients with ELI < 0.6 cm2/ m2, the incidence of aortic valve events was 3 times greater over 5-6 years than in those with larger ELI.

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Overall survival was said to also be better; however, their Figure 1B shows that at 6 years overall survival in the two groups was virtually identical. COMMENT: ELI may be useful in patients with small aortic root (< 2.6 cm) and when the grading of severity is inconsistent between AVA and mean gradient. In the latter instance it may be more prudent to proceed to careful and complete cardiac catheterization and angiography by skilled and experienced cardiologists.. 3. CHARLSON CO-MORBIDITY INDEX

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239 patients, aged > 60 years from the Australian Department of Veterans Affairs, were enrolled from 1988 to 1994 and followed until 2008.14 During the follow-up, 132 patients

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developed severe AS (AVA < 1.0 cm2 or mean AVG > 40 mm Hg). At 10 years, the survival of those with severe AS with conservative management vs AVR was 5 ± 3% vs 50 ± 5% (p < 0.001). The independent predictors of all cause mortality included age adjusted Charlson co-

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morbidity index [hazard ratio (HR) 1.24 ± 95% confidence interval (CI) 1.15-1.34, p < 0.001]; LV dysfunction (HR 1.36, 95% /CI 1.09-1.71), p < 0.01; AVR (HR 0.40; 95% CI 0.28-0.58) p <

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0.001.

COMMENT: The Charlson comorbidity index needs to be an additive feature to Euroscore or STS score in evaluating outcome in AS, and therefore, also in clinical decision making for AVR.

4. PROGNOSTIC VALUE OF MYOCARDIAL FIBROSIS

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Myocardial fibrosis was evaluated from biopsy specimens obtained from the interventricular septum at the time of AVR in 99 patients.15 The relative volume of myocardial

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muscle and fibrous tissue was determined by point counting using a 10 x 10 grid at a total magnification of 100x. The fibrosis index (FI) was calculated by dividing the sum of the fibrotic

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areas by that of the total tissue area and expressed as a percentage: no or mild fibrosis (FI < 20%; group 1), moderate fibrosis (FI 20-50%; group 2) or severe fibrosis (FI > 50%; group 3). The fibrous tissue mass index (FTMI) was estimated as FI x LV mass index/100 (gm2). There was a positive correlation between FTMI and LV size and functional class and negative correlation with LVEF. Hospital mortality was 3%. Patients were followed for 6.2 ± 2 years; those in group 3 had the lowest survival (Figure_2). The fibrosis and structural alterations occurred

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predominantly in the subendocardial layers and was followed by progression to all layers of the myocardium. Patients with “significant coronary artery disease” were excluded.

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COMMENT: The initial location of the fibrosis is in the subendocardium and the subsequent progression suggests fibrosis may be related to myocardial ischemia due to associated CAD and/or LV hypertrophy. Also, see below the results of surgical aortic valve replacement (S:AVR)

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and probably may affect results of transcatheter valve treatmentt. There is a need for uniform measurement and quantification of the amount of fibrosis from gadalonium enhanced images of

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magnetic resonance imaging (MRI). D. MANGEMENT OF AS

1. AORTIC BALLOON VALVULOPLASTY (ABV): POOR RESULTS 900 patients were evaluated from April 2007 to May 2011. 595 (66.1%) were assigned to the medical/ aortic balloon valvuloplasty (ABV) group of whom 354 had ABV and

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241 had only medical therapy.16 In the medical/ABV group, the 30 day mortality was 10.1%; 3 and 12 month mortality was 20% and 45% respectively as evaluated from their figure. In the

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medical/ABV group, the causes of death were known to be cardiac, noncardiac and unknown in 38.9%, 28.1% and 32.8% respectively.

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COMMENT: The data on outcomes in the medical/ABV subgroup is similar to 7 previously published studies of outcomes with ABV17-23 : 5 studies comprising 1, 480 patients showed the hospital/30 day mortality was 9.9%; 17-19, 23 one study showed 6 month mortality was 50%; 22 4 studies showed 1 year mortality ranged from 25-45%;17, 18, 20, 21 3 studies showed the 2 year mortality was 40-65%;18, 20, 21 and 2 studies showed 2 year event-free survival was 19% and 25%.18, 21 2. SURGICAL AORTIC VALVE REPLACEMENT (S:AVR): EXCELLENT RESULTS

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From October 1991-July 2010, 3923 patients had AVR for AS. 1637 (42%) had AVR alone, 2286 (58%) patients had AVR + CABG 24 Their ages were 75 ± 8.1 years vs 70 ±

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11 years. In the AVR + CABG group vs the AVR alone group, hospital mortality was 2.4% vs 1.3% and survival at 1, 5 and 10 years was 91% vs 94%, 83% vs 90% and 43% vs 59%

respectively. There is a large amount of data which is comprehensive and presented survival in

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the overall group and in the propensity matched patients. 10 year survival in propensity matched patients shows the 10 year survival of isolated AS and AS + coronary artery disease (CAD) was

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similar at 55% and 50% respectively. Within the isolated AS group, matched patients had a lower survival than unmatched patients with few comorbidities 55% vs 70%; AS + CAD matched patients had a better survival than unmatched patients with myocardial damage and many comorbidities 50% vs 36% (Figure_3). The authors also concluded: “….Patients with severe AS and CAD risk factors should undergo early diagnostics and should have AVR +

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CABG before ischemic myocardial damage occurs.” COMMENT: The question is how early is early enough? In this or similar age groups the

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incidence of associated CAD is up to 60%;25 in this study, it was 58%. I have suggested that in the asymptomatic patient with severe AS diagnostic coronary contrast angiography followed by

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AVR, may be very valuable in managing patients in this age group 25 if: a) the operative mortality for subsequent AVR alone at an institution is ≤ 1-2% and for AVR + CABG is ≤ 24%. In the present study, it was 1.3% and 2.4% respectively; b) The stented bioprosthesis that is inserted has a documented low rate of SVD out to 20 years (Also please see data on Charlson co-morbidity index 14 and on myocardial fibrosis above);15 and c) It would be important and clinically valuable if the study had described the outcomes up to 10 years of the 741 patients

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who were asymptomatic at baseline and also that of patients who had received 19 mm prosthetic heart valves.

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3. LOW RATE OF COMPLICATIONS OF NON-CARDIAC SURGERY (NCS) IN PATIENTS WITH SEVERE AS

In this study 244 patients with severe AS undergoing NCS were matched to 976

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who had no AS.26 Severe AS was defined as AVA < 1.0 cm2 , and patients had a variety of noncardiac surgeries. Outcomes were evaluated at 30 days after NCS for mortality, postoperative

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MI, heart failure and stroke compared to those with no AS. In the asymptomatic AS group (n = 172), the difference in each of the complications was not significantly different compared to no AS group. In the symptomatic severe AS group (n = 72), the incidence of postoperative MI was 5.6% vs 1.4% in the no AS group, p = 0.009 but the incidence of the other complications was not significant; however, the incidence of a combination of 30 day mortality and postoperative MI

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was higher 8.3% vs 2.7%, p 0.007. The authors stated “the heightened anesthetic management in patients with severe AS is extremely relevant to current surgical practice and represents the norm rather than the exception.”

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COMMENT: Previously, 3 studies with combined 97 patients had similar findings.27-29 The

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National Hospital Discharge Survey from 1996-2002 showed 5,149 patients with a diagnosis of AS had undergone NCS and were matched with 10,284 controls.30 There was no significantly increased risk of death in AS vs controls, the risk of perioperative MI was 3.86% vs 2.03%, p < 0.001 with odds ratio (OR) 1.55, 95% confidence interval 1.27 to 1.90, p < 0.001.30 Several of the studies emphasized careful monitoring during anesthesia induction and procedure and prevention of hypotension. Consideration should be given to monitoring during NCS with use of right heart balloon catheter and intraarterial pressure.

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E. COMBINED AS AND AR IS ASSOCIATED WITH HIGHER EVENT RATE 71 consecutive asymptomatic patients (21 women, age 52 ± 17 years, normal

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LVEF ≥ 0.55) had “at least moderate AS” and “at least moderate AR”.31 At a median follow-up of 8.9 years, 50 patients developed an indication for AVR, 43 had AVR and 33 of the 43

developed symptoms. Event-free survival for the entire patient population at 1, 2, 3, 4 and 6

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years was 82 ± 5%, 62 ± 6%, 49 ± 6%, 33 ± 6% and 19 ± 5% respectively. There were no cardiac deaths.

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COMMENT: The high event rate supports close follow-up of these patients. F. DISCRETE SUBAORTIC STENOSIS (DSS) IN ADULTS 1. NATURAL HISTORY: SLOW PROGRESSION

Data are from 149 patients at 4 centers.32 Longitudinal follow-up data were available for 149 patients, age 20 years Interquartile range (IQR) 18-34, 48% male. 40% had

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associated congenital heart defects, baseline LV outflow tract (LVOT) gradient was 32.3 ± 17 mm Hg which increased by 0.8 ± 0.1 mm Hg/year. Presence of associated congenital heart defect

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was associated with faster progression (p = 0.005), mild AR was common but did not significantly progress over time (p = 0.701). The median intervention-free survival was 16 years;

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the mean age at DDS surgery was 35.1 ± 14 years. Independent predictors for intervention were LVOT gradient ≥ 50 mm Hg, LVOT gradient progression and moderate-to-severe AR. 2. HIGH INCIDENCE OF REOPERATION Data are from 313 patients at 4 centers.33 The patients age was 20.2 years (25-75th

percentile, 18.4-31.0 years), 52% were male, median follow-up was 12.9 years (25-75th percentile, 6.2-20.1 years). There was 1 operative death from heart failure. There were 10 late deaths; 20 year survival was 97%. 80 patients (25.6%) underwent at least 1 reoperation for

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recurrent DSS and 19 required a third operation (1.76% per patient year). Mean time from initial operation to reoperation was 12.0 ± 7.6 years. Predictors for reoperation include female sex (HR

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1.53: 95% CI 1.02-2.30) and progression of left ventricular outflow tract obstruction (HR 1.45: 95% CI 1.31-1.62). Additional myectomy did not reduce the risk for reoperation but increased the risk of complete heart block requiring pacemaker implantation (8.1% vs 1.7%, p = 0.005).

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G. HEYDE’S SYNDROME (HS)

BENEFICIAL EFFECTS IN HEYDE’S SYNDROME AFTER AVR FOR SEVERE AS

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Bleeding in Heyde’s Syndrome is attributed to intestinal angiodysplasia. A retrospective study identified 57 patients who underwent AVR for severe AS who had intestinal angiodysplasia and gastrointestinal bleeding.34 The patients were aged 74 ± 10 years, AVA was 0.7 ± 0.3 cm2. The number of documented episodes of gastrointestinal (GI) bleeding was 4 ± 6 (range 1-27), the mean number of bleeds per patient year was 12. Melena, the most common

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symptom/sign was present in 53%. Intestinal angiodysplasia was located in the right colon in 28%, jejunum 25%, right colon plus another GI tract location in 21%. CABG was also performed

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in 32%. There were 2 operative deaths, none since 1987. The 1 and 5 year survival was 93% and 59% respectively. At follow-up of 4.4 years (range 0.1 – 15 years), 45 patients (79%) had no

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further bleeding. In 12 (21%) patients, the bleeding episodes were reduced from 4.7 ± 7 to 1.9 ± 2 patients per year.

COMMENT: From Heyde’s initial clinical observation in 1958 to 2012, studies have described its fundamental biologic mechanism.35 Of 3.8 million patients discharged from public hospitals in Ireland, the incidence of gastrointestinal bleeding in patients with AS was 0.9%.36 BICUSPID AORTIC VALVE (BAV)

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A.

CARDIAC MAGNETIC RESONANCE IMAGING (cMRI) IS BETTER THAN 2-DIMENSIONAL TRANSTHORACIC ECHOCARDIOGRAPHY (2-D TTE)

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FOR DIAGNOSIS OF BAV. Of 1203 patients who had AV operation, 218 had both preoperative 2D TTE and cMRI; BAV was confirmed in 123 patients.37 Of these 123 patients, 2D TTE confirmed BAV in

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76 (62%), 12 (10%) misidentified it as tricuspid valve and was non-diagnostic in 35(28%). In the same 123 patients, cMRI confirmed BAV in 115(93%), 5(4%) misidentified it as tricuspid

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valve and was non-diagnostic in 3(2%). The difference in identifying BAV by 2D TTE vs cMRI was significant (p < 0.001). In the entire cohort of 218 patients, 2D TTE was diagnostic for valve morphology in 155(71%), cMRI was diagnostic in 212(97%) p < 0.001. MITRAL STENOSIS (MS) A.

EXCELLENT 20 YEAR RESULTS OF CATHETER BALLOON

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COMMISSUROTOMY (CBC) FOR RESTENOSIS AFTER PREVIOUS SURGICAL MITRAL COMMISSUROTOMY

163 patients had CBC (called percutaneous mitral commissurotomy) due to bicommissural

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fusion for restenosis after surgical commissurotomy.38 Good immediate result [valve area ≥ 1.5

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cm2 and mitral regurgitation (MR) ≤ 2/4] was obtained in 135 (83%). In those with good immediate result, the 20 year results were: mortality of 17%, repeat CBC in 18%, and survival without surgery was 33.2 ± 5.5% and good functional result (cardiovascular survival and NYHA Class I/II) was 17.9 ± 4.7% (Figure 4). B.

PROGRESSIVELY INCREASING SIGNIFICANT TRICUSPID REGURGITATION (TR) ON LONG-TERM FOLLOW-UP AFTER SUCCESSFUL CBC FOR SEVERE MS

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A prospective study of 299 patients showed that after successful CBC,39 TR regressed. However, 56 patients developed significant TR (grade ≥ 3 on echocardiography/

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Doppler) during follow-up (median 12 years, IQR 8.0 – 18 years). The increase was timedependent; at 8, 12 and 18 years after CBC significant TR were present in 9.4%, 19.8% and 35.2% respectively. Atrial fibrillation (A. Fib), TR grade ≥ 2 before CBC, and mitral valve

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restenosis were important factors for de novo development of late TR. MITRAL REGURGITATION (MR)

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A. RESUSITANT FROM SUDDEN DEATH: TRIAD OF BILEAFLET MITRAL VALVE PROLAPSE (MVP) IN WOMEN, ST-T WAVE CHANGES ON ECG AND FREQUENT COMPLEX VENTRICULAR ECTOPIC ACTIVITY

24 of 1,200 patients in the Mayo Clinic Long QT Syndrome/Genetic Heart Rhythm Clinic had idiopathic out-of-hospital cardiac arrest (i.e. negative for ischemia,

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cardiomyopathy, and channelopathy). 40 All had implantable cardioverter-defibrillators (ICD). Out-of-hospital cardiac arrest had occurred in 22 (92%). 10/24 (42%) had bileaflet MVP and

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comparing these to those with normal mitral valves, the incidence of women was 90% vs 50% (p = 0.04), and had higher incidence of biphasic or inverted waves 77.8% vs 29% (p = 0.04). On

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Holter monitoring, they had a higher prevalence of: a) Ventricular bigeminy 100% vs 10%, (p < 0.0001); b) Ventricular tachycardia 78% vs 10% (p = 0.006); and c) Premature ventricular contractions originating from the outflow tract alternating with the papillary muscle or fasicular region 78% vs 28%, (p = 0.02) (Figure _5). Over a median follow-up of 1.8 years (range 0.1 to 11.9 years) after ICD placement, 13 of 24 (54%) patients received appropriate ICD shock for ventricular fibrillation. Only bileaflet MVP was associated with ventricular fibrillation requiring ICD therapy (p = 0.028).

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COMMENT: Very important data. It should be emphasized that no patient of the 24 idiopathic out of hospital cardiac arrest had prolapse of only one leaflet.

≥ 65

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B. LONGITUDINAL OUTCOMES OF MITRAL VALVE REPAIR (MVrep) IN PATIENTS YEARS OF AGE

Data are presented from the Society of Thoracic Surgeons (STS) database in

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14, 604 who had MVrep from 1991 to 2007.41 Patients were aged 73.3 ± 5.5 years, LVEF was 0.54 ± 0.13, 55.8% were female, 8.4% were non-Caucasians. Operative mortality was 2.59%,

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follow-up was 5.9 ± 3.9 years (range 1 to 18 years). The 10-year actuarial survival was 57.4%. The 10-year actuarial rates of mitral reoperation, heart failure, bleeding, and stroke were 6.2%, 30.1%, 15.3% and 16.4%, respectively.

COMMENT: Interesting data. Those that were important and clinically valuable but were not presented included: a) The number of patients who had mitral valve replacement (MVR) during

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the same time period; b) The confidence intervals of survival and of events; c) The incidence and severity of recurrent MR. This is likely to be underestimated by evaluating the reoperation rate;

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and d) The mortality and incidence of heart failure were “high”. Therefore, there is a need to document the extent and intensity of medical treatment on follow-up and at baseline the

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incidence of associated CAD based on findings from coronary arteriography, risk factors for CAD, the incidence of moderate and severe MR, the frequency and severity of renal dysfunction and the causes of death (Please also see late outcomes of MVrep below). C. MVP WITH A NEAR 100% MVrep RATE From 2002 to 2010, MVrep was performed by a single surgeon in 744 consecutive patients, 1 patient had to be converted to MVR.42 Patients were aged 58 ± 13 years (range 12-90), 21% were ≥ 70 years, LVEF was 0.55 ± 0.09, 12% were in NYHA FC III/IV,

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MR was moderately severe in 6.5%, severe in 93.5%. 30 day mortality was 0.9%. 1 and 5 year survival was 99.2 ± 0.3% and 97.4 ± 0.8%. 70% had late follow-up echocardiography at follow-

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up time of 1.5 ± 1.1 years (range 7-2527 days) which showed recurrent ≥ 2 + MR at 7 years of 9%. D. LATE (20 YEAR) OUTCOMES OF MVrep

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From 1985 to 2004, all 840 patients who had MVrep for “degenerative” MR are reported.43 Their age was median of 60 years IQR 50-68, NYHA FC I, II, III and IV in 15.1%,

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36.7%, 36.8% and 11.3% respectively, LVEF ≥ 0.60 in 60.1%, severe MR in 95%, moderate in 5%. STS risk score was 1.5% (95% CI 0.3%-5.5%). 30 day mortality was 4/840 (< 0.5%). Follow-up times ranged from 0 to 26 years, median was 10.4 years IQR , 7.4 to 13.7 years. Clinical follow-up was complete in 98.4% of patients. Echocardiographic follow-up extended from 0 to 26 years, median IQR of 10.3 years (7.5 to 13.3 years) and was complete in 94.9%. By

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echocardiography/Doppler, valve function was evaluated and data were presented at 5-10 years, 10-15 years, 15-20 years and > 20 years in 97%, 94%, 90% and 76%. Outcomes at 10 & 20 years

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are shown in Table 1.

COMMENT: Very impressive follow-up data that are comprehensive. Excellent outcomes.

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Note: The low STS risk score and 52% of patients were in NYHA FC I and II. E. LATE OUTCOMES AFTER DOUBLE-ORIFICE MVrep COMBINED WITH RING ANNULOPLASTY

The edge-to-edge (E-to-E) procedure produces a double-orifice (DO) mitral valve.

From 1993 to 2000, 174 patients with severe degenerative MR had E-to-E plus ring annuloplasty.44 They comprised 24.5% of patients who had MVrep during this time period. They were aged 52 ± 18 years, 71% of patients were in NYHA FC I/II; A Fib in 17.2% . Follow-up

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was 11.5 ± 2.53 years (range 1.1 to 17.6 years) and was complete in 169 (97.1%) 55 of whom had an echocardiogram at the authors institution and in 114 within the previous 6 months by the

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referring local cardiologist. MR was due to anterior, posterior and bileaflet prolapse in 20.6%, 5.7% and 73.5% respectively. There were no hospital deaths, actuarial survival at 14 years was 86.9 ± 3.37 and freedom from cardiac death was 95.8 ± 1.54%. Freedom of reoperation was 89.6

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± 2.51%. Mitral stenosis requiring reoperation was detected in 1 patient (0.6%). MV area was 3.2 ± 0.4cm2, MR was absent in 24.8%, mild in 49.1%, moderate in 12.4%, and moderate to severe

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in 3.5%. Recurrence of MR ≥ 3+ occurred at a median of 8.2 years (IQR 2.8 – 10.7 years); the only predictor of recurrence of MR ≥ 3+ was residual MR greater than mild at hospital discharge. The incidence of NYHA FC I, II & III was 66.2%, 28.9% and 4.7% respectively (p = 0.0001 compared to preoperative values).

INFECTIVE ENDOCARDITIS (IE) PERSISTENT POSITIVE BLOOD CULTURES AT 48-72 HOURS AFTER

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A.

INITIATION OF ANTIBIOTIC TREATMENT FOR LEFT-SIDED IE IS

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ASSOCIATED WITH INCREASED IN-HOSPITAL MORTALITY. Of 256 patients with positive blood cultures, 89 (35%) had persistent positive

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blood cultures at 24-72 hours which was associated with a doubling of in-hospital mortality [OR 2.1; 95% CI 1.2-3.6].45 Other independent predictors of in-hospital mortality were staphylococcal infection (OR 3.3), renal failure (OR 2.9), heart failure (OR 2.8) and age (OR 1.026). COMMENT: 43% of the 99 patients with prosthetic valve endocarditis had positive blood cultures at 48-72 hours compared with 29% of patients with native valve endocarditis. About 90% of patients with streptococcal viridans infection had negative blood cultures at 48-72 hours.

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B.

NEUROLOGIC COMPLICATIONS OF IE: MOST EMBOLIC EVENTS OCCUR DURING THE FIRST 7 DAYS OF ANTIBIOTIC THERAPY

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Data are from a prospective multicenter study from 8 centers in Spain from 19842009. Of 1345 consecutive episodes of left-sided IE, 340 (25.3%) had ≥ 1 neurologic

complication.46 Ischemic events were the most frequent of these complications and occurred in

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192 of 340 (56%) patients. Overall mortality was 30%; neurologic complications accounted for 45% of the deaths. Antibiotic therapy reduced the neurologic complications by 33 to 75%.

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Importantly, 163/192 (85%) ischemic events while on antibiotic therapy occurred in 133/163 (82%). Of these, ischemic events occurred ≤ 7 days of starting antibiotic therapy. Surgery was performed in only 523/710 (39%) of those in whom it was indicated. C.

THE ADDITION OF 18 F-FDG PET/CT TO ECHOCARDIOGRAPHY IMPROVES THE DIAGNOSIS OF PROSTHETIC HEART VALVE ENDOCARDITIS (PVE)

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72 patients suspected of PVE were prospectively studied;47 36 (50%) of whom exhibited abnormal FDG uptake around the site of the PHV. The sensitivity, specificity, positive

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predictive value, negative predictive and global accuracy of FDG uptake were 73%, 80%, 85%, 67% and 76% respectively. Adding abnormal FDG uptake around the PHV increased the

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sensitivity of the modified Duke criteria at admission from 70% to 97%, p = 0.0008; the result was due to a significant reduction (p < 0.0001) in the number of possible PVE cases from 40 (56%) to 23 (32%).

COMMENT: The accurate diagnosis of PVE is clinically very important but can be problematic. Cardiac PET/CT could become a very useful additional diagnostic test. TRANSCATHETER VALVE THERAPY (TVT) AORTIC

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A.

UPDATED STANDARDIZED ENDPOINT DEFINITIONS FOR TRANSCATHETER AORTIC VALVE IMPLANTATION 48 HISTOPATHOLOGY OF EMBOLIC DEBRIS CAPTURED DURING AORTIC TVT.

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B.

40 patients underwent aortic TVT with use of a dual fitter-based embolic

protection device (Montage Dual Filter System, Claret Medical, Inc.) 49 The debris had 7

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different histopathologic characteristics (Table 2). There were different types of thrombus (Figure 6 ).

C.

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COMMENT: An important study.

TVT FOR STRUCTURAL VALVE DETERIORATION (SVD) OF BIOPROSTHETIC PHV: DATA FROM GLOBAL VALVE-IN-VALVE REGISTRY Data are from 202 patients in 38 cardiac centers aged 77.7 ± 10.4 years, male

52.5%. They had received Core Valve (n = 124) and Edwards-Sapien valve (n = 78) for TVT.50

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The mode of failure of the bioprosthesis was stenosis in 42%, regurgitation in 34%, stenosis plus regurgitation in 24%. Procedural success rate 93.1%; adverse outcomes included device mal-

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position in 15.3% and ostial coronary obstruction in 3.5%. Stroke rate was 2%, AR grade ≥ 2+ in 5%, mean AVG was 15.9 ± 8.6 mm Hg. 30 day and 1 year mortality was 8.4% and 14.2%

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respectively. Preprocedure, 94.2% were in NYHA FC III/IV. At 1 year, 49% and 35.1% were in NYHA FC I and II respectively. COMMENT: An important direction of TVT with impressive early results. A review documented in detail outcomes of this procedure.51 It is still a very early stage of this procedure; inappropriate conclusions that may result in changes in clinical practice should be avoided. D. WOMEN HAVE BETTER SHORT-AND LONG-TERM SURVIVAL WITH TVT

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Consecutive 641 patients undergoing aortic TVT in two centers in Canada were evaluated;52 329 (51.3%) were women 312 were men. Balloon-expandable valves were used in

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97% with trans-apical approach in 51.7% in men and 38.1 % of women. Porcelain aorta was present in 29.2% of women and 12.0% of men, p < 0.001. Women had more major vascular complications (12.4% vs 5.4%, p = 0.0003) needed more blood transfusions (9.5% vs 3.6%, p =

1 year and 72.1% vs 61.7% at 2 years, p = 0.007.

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MITRAL

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0.005) but had a lower 30 day mortality. The survival in women vs men was 82.7% vs 72.5% at

A. IMMEDIATE EFFECTS OF REDUCTION OF MR BY MITRAL CLIP ON LV REMODELING AND LOADING CONDITIONS.

33 patients, age 78 ± 10 years with functional (45%), degenerative (48%) or mixed (6%) MR.53 were studied acutely while still under anesthesia immediately before and

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after placement of Mitral Clip. Standard right heart catheterization and LV catheterization using conduction catheter were performed which allowed obtaining continuous measurement of LV

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pressure and volume and allowed measurement/calculation of LV afterload, preload, enddiastolic and end-systolic stress, contractility, myocardial energetics and hemodynamics. The

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authors summarized their findings as: “1) Reduction of MR by TVT results in an acute increase of LV afterload and reduction of preload. A significant increase in forward cardiac output and decrease of pulmonary pressures indicates the increase in afterload is outweighed by enddiastolic unloading; 2) Despite a decline in LVEF, LV contractility is not significantly affected; 3) LV total mechanical energy remains unchanged and therefore myocardial oxygen consumption is not expected to increase; and 4) The beneficial hemodynamic changes with

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preserved LV contractility reverses LV remodeling by reducing end-diastolic volume. At 3 months, NYHA functional class and LV dilatation were improved.”

PROSTHETIC HEART VALVE (PHV)

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COMMENT: Sophisticated and excellent study.

A. SOCIETY OF THORACIC SURGERY (STS) CLINICAL PRACTICE GUIDELINES:

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EXECUTIVE SUMMARY 54

COMMENT: These guidelines present the viewpoint of STS with regard to the surgical aspects

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of heart valves and of ascending aorta and include recommendations of the surgical aspects of aortic root, ascending aortic dissection, ascending aorta and aortic arch. The STS guidelines have 83 Class I recommendations of which 6 (7.2%) are based on Level of Evidence A. Moreover, two of the recent randomized trials that have been cited have significant problems.55, 56 Of the 145 recommendations, the Level of Evidence was C

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in 62%.

B. ANTICOAGULATION OF OLDER PATIENTS RECEIVING AVR WITH BIOPROSTHETIC VALVES: IS ASPIRIN ALONE ADEQUATE?

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Data are from 25, 656 patients aged ≥ 65 years in the 2004-2006 STS database,57

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their median age was 77 years (IQR 72 to 81 years), 39.4% were women. 13,458 (52.5%) patients had a prior history of ≥ 1 risk factor for early thromboembolism at hospital discharge: atrial fibrillation in 41.1%, thromboembolism in13.6% or LVEF < 0.30 in 4.8%. At hospital discharge, 12,457 (48.6%) received aspirin only (Group A), 2,999 (11.7%) received warfarin only (Group B) and 5972 (23.3%) received aspirin plus warfarin

(Group C). The 3 month

incidence of death in these 3 groups was 3.0 %, 4.0% and 3.1% respectively; and of bleeding was 1.0%, 1.4% and 2.8% respectively.

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COMMENT: The answer is yes unless there is an associated co-morbid condition for which there is a widely accepted indication for warfarin therapy. There is a very recent randomized

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trial indicating benefit regarding improved graft patency with use of aspirin + clopidogrel in patients undergoing off-pump CABG. 58, 59 Should we apply this finding to patients undergoing AVR + CABG? I believe the answer is also yes at the present time.

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C. PREVIOUS CABG DOES NOT INCREASE MORTALITY OR MORBIDITY OF REOPERATIVE VALVE SURGERY

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1093 consecutive patients underwent reoperative cardiac surgery between 2000 and 2010;60 of whom 363 had isolated reoperative valve surgery. Their age was 62 ± 16 years; 38.8% were female; the time from previous surgery was 8.6 ± 7.8 years, 15% of reoperative surgery occurred within 1 year of initial operation. In group A patients (n = 133), the previous surgery had included CABG in group B (n = 230), patients had not had previous CABG. In

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Group A patients, 94% had patent grafts. Operative mortality was 4.1%. In propensity matched patients, there was no statistically significant difference between the 2 groups for mortality or

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morbidity. Group A patients had a lower 5 year survival than Group B patients but in propensity matched patients the difference was not statistically significant. Multivariate predictors of

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decreased survival were severe pulmonary hypertension (OR 2.76), diabetes mellitus (OR 2.01), NYHA Class III or IV (OR 1.69), Logistic Euro Score (OR 1.04), peripheral vascular disease (OR 0.55).

D. OUTCOMES OF DAVID VALVE-SPARING AORTIC ROOT REPLACEMENT IS SIMILAR IN THOSE WITH BI- AND TRICUSPID AORTIC VALVES 233 patients (BAV in 27%, Marfan Syndrome 40%) underwent Tirone David’s valve-sparing aortic root replacement from 1993 to 2009.61 Survival at 5 and 10 years was 98.7%

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± 0.7% and 93.5% ± 5.1%. At 5 and 10 years, there was no statistically significant difference between patients with bi- and tricuspid aortic valves in survival, reoperation, SVD, or any other

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functional or clinical end-points including those with associated connective tissue disorder. E. LONG-TERM SURVIVAL AFTER S:AVR AMONG HIGH-RISK “ELDERLY” FROM STS DATABASE 1991-2007

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Data on 103,500 Medicare-linked S:AVR patients from 1999 to 2007 are

presented.62 Patients were categorized by procedure type (AVR, AVR+CABG) and age (65-69,

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70-79, ≥ 80 years). Operative mortality of AVR (n = 43, 809) and of AVR+CABG (n = 59, 691) was 3.9% and 5.0% respectively. For patients in the 65 to 69, 70 to 79 and ≥ 80 years of age, the median survival after AVR was 12.8, 9.2 and 6.2 years respectively and for AVR+CABG was 10.4, 8.2 and 5.9 years respectively. Median survival was also presented by categorization to several high-risk groups. Severe lung disease and renal failure were each associated with a ≥

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50% reduction in median survival among all age groups. The survival is said to be “excellent” and was matching that of a “similarly aged US population.”

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COMMENT: Data is important. However, that which is clinically valuable but that was not presented included: a) Operative mortality in the 3 subgroups characterized by age: b) IQR of the

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median survival; c) Survival curves do not present in Text or figures the confidence intervals and numbers of patients at-risk; and d) Data that matches the survival to that of the US population. Also, note one criterion of renal failure in the STS database (creatinine > 2.0 mg/L) does not precisely delineate the extent of renal dysfunction.

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LEGENDS TO THE FIGURES FIGURE 1:SURVIVAL OF ELDERLY PATIENTS WITH AS IN A COMMUNITY

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Survival during management of patients with aortic stenosis (AS) without aortic valve replacement according to baseline aortic valve area (AVA). The numbers along each curve indicate the survival at 5 and 8 years. Patients with mild AS (orange) and moderate AS (green) have similar survival. There is a higher mortality in those with severe AS (blue) AVA less than 1.0 cm2., with permission, from Malouf et al (9).

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FIGURE 2: Actuarial freedom from cardiac death at 10 years according to myocardial fibrosis grade 1 (orange) [Fibrosis Index (FI) < 20%], grade 2 FI 20-50% (green) or severe > 50% (blue). Reprinted, with permission, from Milano et al (15)

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FIGURE 3: SURVIVAL OF PROPENSITY-MATCHED AND UNMATCHED PATIENTS Survival of patients with isolated AS with few comorbidities (top blue). This is compared with matched isolated AS and few (non-CAD) comorbidities (middle blue curve) and matched AS+CAD (middle red curve). These are all contrasted with patients having AS and CAD with myocardial damage and many comorbidities, lower curve (red). AS = Aortic Stenosis, CAD = Coronary artery disease. Vertical bars represent confidence limits equivalent to ± 1 standard error. Reprinted, with permission, from Beach et al (24).

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FIGURE 4: 20 YEAR OUTCOMES AFTER CBC: WITHOUT FURTHER SURGERY (LEFT PANEL) AND GOOD FUNCTIONAL RESULTS (RIGHT PANEL). Data are after catheter balloon commissurotomy (CBC) for recurrent mitral stenosis after surgical mitral commissurotomy (CBC). Reprinted, with permission from, Bouleti et al (38).

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FIGURE 5: MALIGNANT BILEAFLET MVP IN PATIENTS WITH PREVIOUS CARDIAC ARREST A phenotype of life-threatening ventricular arrhythmias with: i) Bileaflet mitral valve thickening and mitral valve prolapse (MVP) in women; Systolic and diastolic parasternal long-axis view of the heart are shown (A); ii) T-wave changes in the inferior leads (B); and iii) Frequent ventricular ectopic activity with premature ventricular beats of outflow tract origin alternating with papillary muscle or fascicular origin (C). Reprinted, with permission, from Sriram et al (40). FIGURE 6: TYPE OF THROMBUS IN EMBOLIC DEBRIS WITH TVT TVT = Transcatheter aortic therapy for aortic stenosis. A, Platelet-rich acute thrombus with focal presence of neutrophils. B, High-power magnification of the boxed area in A. C, Organizing chronic thrombus. D, High-power magnification of the boxed area in C with the presence of spindle-shaped cells and focal sparse macrophages with occasional capillaries (arrows). E and F, High-power images of an organizing thrombus with interspersed fibrin and proteoglycans (green in Movat-stained F). A to E, H&E stained sections; F, a Movat pentachrome-stained section. Reprinted, with permission, from Van Mieghem et al (49).

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TABLE 1: Survival Estimates and Freedom From Adverse Events at Various Time Intervals From

Outcomes

10 years

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(95% CI)

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competing Risk Models (Top) and From Parametric Survival Regression Models (bottom)

Competing risk*

Cardiac death (nonvalve)

(95% CI)

100%

100%

3.7 (2.6-5.1)

11.3 (8.0-15.7)

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Valve-related death

20 years

2.8 (1.9-4.2)

7.8 (5.2-11.7)

7.4 (5.9-9.3)

23.7 (18.9-29.2)

4.1 (3.0-5.6)

5.9 (4.3-8.0)

82.1 (76.5-86.5)

51.9 (43.0-60.6)

85.8 (84.5-86.9)

54.8 (51.8-57.8)

95.9 (94.4-97.0)

94.1 (92.0-95.7)

95.5 (94.8-96.2)

90.7 (88.9-92.2)

90.4 (89.3-91.4)

69.2 (65.8-72.5)

Endocarditis

99.0 (98.5-99.3)

98.5 (97.8-99.0)

Thromboembolism

90.8 (89.7-91.7)

85.7 (84.1-87.3)

Noncardiac death Reoperation†

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Alive and reoperation-free† Freedom from other outcomes All-cause mortality

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Mitral reoperation Mitral regurgitation

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Severe

Moderate/severe

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TABLE 2: Distribution of Debris Found in the Overall Patient Cohort Histopathologic Characteristics Calcium + valve tissue + thrombus

2

Calcium + valve tissue

3

Valve tissue

4

Thrombus

5

Thrombus + necrotic core

6

Thrombus + collagenous tissue

7

Collagenous tissue

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1

No. of Cases (n = 30) 3

2

3

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8

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CI indicates confidence interval.

*These are proportion of patients, freedom = 100 – (proportion of patients)

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†Reoperation on the mitral valve.

Adapted from David TE et al, reference (43). Reprinted, with permission from Van Mieghem (49).

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AC C

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AC C

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TE D

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AC C

EP

TE D

M AN U

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AC C

EP

TE D

M AN U

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RI PT

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AC C

EP

TE D

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AC C

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TE D

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