YEAR IN CARDIOLOGY SERIES
The Year in Valvular Heart Disease
Shahbudin H. Rahimtoola, MB, FRCP, MACP, MACC, DSc (Hon)1,*
Griffith Center, Division of Cardiovascular Medicine, Department of Medicine, LAC + USC Medical Center, Keck School of Medicine at USC, Los Angeles, California.
Manuscript received September 18, 2006;
revised manuscript received November 2, 2006,
accepted November 6, 2006.
* Reprint requests and correspondence: Dr. Shahbudin H. Rahimtoola, University of Southern California, 2025 Zonal Avenue, GNH 7131, Los Angeles, California 90033.
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Normal Valves: Development and Structure
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Normal human semilunar valve development.
Ninety-one semilunar valves from fetuses, neonates, children, and adults were studied (1). Valvular endothelial cells express an activated phenotype throughout gestation. Valvular interstitial cell density, proliferation, and apoptosis are higher in fetal than adult valves indicating matrix remodeling whereas in adults it is a quiescent fibroblast-like phenotype (Fig. 1). Elastin significantly increases postnatally (Fig. 2). The authors concluded: "Fetal valves possess a dynamic/adaptive structure and contain cells with an activated/immature phenotype. During postnatal life, activated cells gradually become quiescent, whereas collagen matures."
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Figure 1 Endothelial Cells of Fetal Valves Have an Immature/Activated Phenotype
(A) CD31-positive fetal valvular endothelial cells (VECs) in the second and third trimesters and VECs in children’s valves consistently expressed nonmuscle myosin produced by embryonic or activated cells (SMemb), matrix metalloproteinase (MMP)-1, MMP-13, and cell adhesion molecules ICAM-1 and VCAM-1, whereas normal adult VECs mostly had negligible expression levels of these proteins. Bar = 50 µm. Magnification 400x. (B) Percent of endothelial cells positive for maker. *Significant differences in protein expression in adult valves (p < 0.001). From Aikawa et al. (1).
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Figure 2 Schematic Representation of Natural History of Cardiac Valve Remodeling by Interstitial Cells
Schematic summary of cardiac valve remodeling in fetal valves according to the findings of the present study. Activated/immature cell phenotypes and collagen remodeling in gestation were followed after birth by decreased cell activation and eventually, in adults, by quiescence. These cellular changes were accompanied by increased collagen fiber thickness and alignment. Thin lines = thin, immature collagen fibers; thick lines = thick, mature collagen fibers. From Aikawa et al. (1). Abbreviations as in Figure 1.
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Familial Aggregation of Calcific Aortic Stenosis (AS)
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The geographic distribution of 2,527 operated patients with calcific AS was heterogeneous in areas in France, with frequencies of 1.13 to 9.38 of 1,000 inhabitants in different parishes (Fig. 3). From parishes with the highest rate of operated AS, there were 5 families in whom 
3 siblings were affected. Genealogical examination traced a common ancestor within 13 generations in one of the families in whom 48 patients were derived from 34 nuclear families (2).
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Figure 3 Map of the Repartition of Operated CAVS in the Western Part of France
Disease frequency was calculated for each parish by comparing the number of native cases of operated calcific aortic valve stenosis (CAVS) to the population living in the village. Population was estimated from the mean of the censuses performed in 1926, 1931, and 1936. This map shows an obvious spatial heterogeneity. Two clusters of high frequency can be described, 1 on the northern part of the map and 1 between the southern part of Nantes and La Roche-sur-Yon and between the Atlantic coast and Cholet, corresponding to a well-known isolate called "vendee-cholletaise." The letters represent parishes in which familial aggregation of the disease has been identified. From Probst et al. (3).
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Comment.
These findings suggest a genetic component to calcific AS in some patients. An earlier study had shown the familial relative risk of death per year in those aged <65 years was 4 times higher in first degree relatives of those with aortic valve (AV) disease documenting a heritable component (3).
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Mechanisms of Valvular Heart Disease (VHD)
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Low-density lipoprotein receptor-related protein (Lrp5).
Low-density lipoprotein receptor-related protein, osteocalcin, and other osteochondrogenic differentiation markers are increased in calcified AV by protein and gene expression (p < 0.001) (4). Sox9, Lrp5 receptor, and osteocalcin were increased in myxomatous mitral valves (MV) by protein and gene expression (p < 0.001). Microcomputed tomography was positive in the calcified AV and negative in the myxomatous MV (Figs. 4 and 5).
The authors concluded: "The mechanisms of VHD involve an endochondral bone process that is expressed as cartilage in MV and bone in AV. Up-regulation of the Lrp5 pathway may play a role."
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Figure 4 Immunohistochemistry of the Human Mitral Degenerative Valves and Calcified Tricuspid and Bicuspid Aortic Valves for Non-Collagenous Bone Matrix Synthesis
Control valve, degenerative mitral valve (arrow points to hypertrophic chondrocytes), calcified aortic valves (arrow points to positive stain), and bicuspid aortic valve (arrow points to positive stain) (magnification 25x). Insert within each photo is high-power magnification to demonstrate cellular staining (magnification 40x) (A) Bone sialoprotein strain. (B) Osteoponton stain. (C) Osteocalcin stain. From Caira et al. (4).
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Figure 5 Immunohistochemistry of the Human Mitral Degenerative Valves and Calcified Tricuspid and Bicuspid Aortic Valves for Endochondral Signaling Markers Low-Density Receptor Protein 5/Wnt and Proliferating Cell Nuclear Antigen
Control valve, degenerative mitral valve (arrow points to hypertrophic chondrocytes), calcified aortic valves (arrow points to positive stain), and bicuspid aortic valve (arrow points to positive stain) (magnification 25x). Insert within each photo is a high-power magnification to demonstrate cellular staining (magnification 40x). (A) Lipoprotein receptor-related protein 5 stain. (B) Wnt 3 stain. (C) Proliferating cell nuclear antigen strain. From Caira et al. (4).
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Human atrial ion channel and transporter subunit gene expression.
Messenger ribonucleic acid expression was quantified in atrial tissues from 7 sinus rhythm-VHD, 11 atrial fibrillation (AF-VHD), and 11 control subjects (5). Principal findings were: VHD produces important changes in cardiac ion-channel gene expression, discrete ion-channel subunit changes differentiate patients with VHD who develop persistent AF from those who do not.
Extravalvular cells in "degenerative" valves.
Studies of AS and bioprosthetic valves showed that endothelial progenitor cells, dendritic cells, T-lymphocytes, and macrophages were much higher in bioprosthetic than in AS (6) (Table 1).
Comment.
These findings suggest pathogenetic factors involved in degenerative native and bioprosthetic AS are probably different.
Cell death is autophagic.
Calcific AS valves showed much higher scores of calcification, inflammation, and ubiquiting labeling than control valves (7). TUNEL-labeled cells were rarely found; thus, the main cell death mechanism in AS is autophagy rather than apoptosis.
Animals that may develop AS.
Apolipoprotein-E-deficient mice had AV sclerosis (8), which showed bone marrow-derived cells that were positive for osteoblast-related markers near the sites of ectopic calcification.
New Zealand white rabbits with experimental hypertension developed AV sclerosis (9).
Role of matrix metalloproteinases in human AV disease.
Both AS and aortic regurgitation (AR) showed similar histologic signs of extracellular matrix remodeling, although calcification, inflammatory cells, and capillaries were more severe in AS than in AR. Increases in matrix metalloproteinase-9 and -3 demonstrated an inflammatory state that was greater in severe AS (10).
Metabolic syndrome (MetS) increases the risk of AV calcification.
Aortic valve calcification was assessed by electron beam computed tomography (EBCT) in 6,780 MESA (Multi-Ethnic Study of Atherosclerosis) participants (MetS [n = 1,550], diabetes mellitus [n = 1,016], or neither [n = 4,024]) free of clinical cardiovascular disease at baseline. Follow-up showed that the prevalence and the adjusted relative risk of AV calcification was increased in MetS and with increasing number of MetS components (11) (Table 2).
Influence of MetS on outcomes in AS.
Of 105 patients, with mean aortic valve area (AVA) 1.08 followed-up for 28 months, linearized progression was "twice as fast" (–0.14 vs. –0.08), 3-year event-free survival was lower (44 vs. 69) in 40 (38%) with MetS (12). In multivariate analysis, MetS was an independent predictor of stenosis progression (p = 0.006) and event-free survival (odds ratio [OR] 3.85, p < 0.001).
Comment.
Concerns include: 1) is it appropriate to calculate annual linearized rate of progression when echocardiograms may only have been obtained 6 months apart, there were almost no events in the first year indicating non-linearity and follow-up was 3 years or less?; 2) patients’ clinical condition (e.g., symptoms, functional class, left ventricular ejection fraction [LVEF], and so on) at baseline were not provided, and 7 of 8 deaths were not related to AS; 3) many patients had severe AS at baseline; the reason(s) why 45 AV replacements (AVRs) were performed 1 year later was not described.
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AS
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Valve calcification as marker for severity is inaccurate.
Calcification score from EBCT for AV calcium content in 61 patients with AS and AVA of 0.7 to 2.0 cm2 (13) showed AV Agatston score "did not correlate strongly" with AVA (r = –0.34, p = 0.0007). The poorest correlation was noted for those patients with moderate and severe AV calcification.
Flow-dependent changes in AVA are real.
An in-vitro study (14) using particle image velocimetry (PIV) in bioprosthetic valves showed good agreement with Doppler (DOP)-derived effective orifice area (EOA) (r2 = 0.94). When stroke volume was increased from 20 ml to 70 ml, there were substantial and similar increases by both methods: +52% for EOADOP versus +63% for EOAPIV
. The authors concluded: flow-dependent changes in EOADOP are real and are due to "unsteady effects" at low flow rates and/or to changes in valve leaflet opening.
High incidence of vascular atherosclerosis in AS.
In 282 patients with severe calcific AS, the incidence of severe obstructive coronary atherosclerosis (59%) and of extracranial cerebral arteries (16%) was significantly associated (p = 0.005) (15).
Improvement in LVEF after AVR in low gradient severe AS is not related to "contractile reserve.".
In 66 previously reported patients with preoperative LVEF 
0.40, 46 (70%; Group I) had "contractile reserve" (increase of left ventricular [LV] stroke volume by 20% calculated by echocardiography/Doppler) and 20 did not (30%; Group II) (16). After AVR, LVEF increased by 0.10 in 38 (83%) patients in Group I and in 13 (65%) patients in Group II; mean increase of LVEF was similar in the 2 groups (19 ± 10% vs. 17 ± 11%, p = 0.54). On multivariate analysis, LVEF improvement was related to multivessel coronary artery disease, p = 0.05 and baseline mean pressure gradient (>30 mm Hg), p = 0.01, but not to contractile reserve.
Comment.
Uncertain if coronary artery disease was revascularized at time of AVR?
Poor outcomes without AVR in older symptomatic patients.
A total of 124, age 60 years (73 of 124, 59% age 80 years) with severe AS (mean AV gradient 50 mm Hg or AVA <0.8 cm2) and LVEF 0.50 in 69.9% were evaluated. Forty-nine (39.5%) had AVR, 30-day mortality was 4.1%. At 1 year, survival with AVR versus no AVR in the subgroup age 80 years (in whom LVEF 0.50 in 63.9%) was 87.5% versus 49.1%, respectively (p = 0.006) (17). Aortic valve replacement was associated with a large mortality reduction, adjusted OR 0.39 (95% confidence interval [CI] 0.22 to 0.67).
Comment.
Even symptomatic octogenarians with severe AS have a better survival with AVR.
Good outcomes after AVR for severe AS with reduced LVEF.
One-hundred fifty-five consecutive patients with AVA 1.0 cm2, LVEF 0.30, age 72 ± 9 years, and New York Heart Association (NYHA) functional class III or IV in 89% underwent AVR (with coronary artery bypass grafting in 16%, abnormal coronary angiograms in 41%) (18). Operative mortality was 12%. The 5-year survival was 71%; 31 of 50 (62%) patients died of non-cardiac causes; 80% had an increase of LVEF (from 0.25 ± 0.05 to 0.36 ± 0.12). In 45%, LVEF had increased by >0.10, those with an early increase of LVEF >0.10 had a better 10-year survival (Fig. 6), and at 1 year 3% were in NYHA functional class III/IV (vs. 89% preoperatively).
Comment.
After successful AVR, more than half of the deaths were due to "non-cardiac" causes, and since 89% were in NYHA functional class III or IV at baseline, it is important not to wait for severe symptoms before performing AVR. Improvement of LVEF of >0.10 after AVR was associated with a better 10-year survival, and 97% of the survivors were asymptomatic or minimally symptomatic emphasizing the need to perform AVR before the onset of moderate/severe LV dysfunction so that postoperatively the patients will have higher LVEF.
Value of quantitative exercise Doppler echocardiography.
Sixty-nine asymptomatic patients age 66 ± 12 years with severe AS (AVA <1 cm2) underwent quantitative exercise echocardiography/Doppler (19). Follow-up was 15 ± 7 months; 18 of 26 (69%) with abnormal response to exercise had symptoms, death, or AVR. By multivariate Cox regression analysis, independent predictors of cardiac events were an increase of mean AV gradient by 18 mm Hg during exercise (p = 0.0015), an abnormal exercise test (p = 0.0026), and AVA <0.75 cm2 (p = 0.0031). Exercise echocardiography/Doppler provided incremental prognostic value over resting echocardiographic and exercise electrocardiographic parameters.
Functional mitral regurgitation (MR) improves after AVR.
Four hundred eight patients, age 70 years, underwent isolated AVR (20); 338 patients had no/mild MR (Group I); 70 had moderate MR (Group II) in whom MR was functional in 21.4%. On multivariate analysis, moderate MR was an independent risk factor impacting long-term survival; in groups I and II, survival at 10 years was 14.6% versus 40.1% (p = 0.04). Mitral regurgitation worsened or persisted in those with intrinsic MV disease but improved in 81.8% of those with functional MR.
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AR
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Long-term outcome of surgically treated AR.
One hundred seventy patients with severe isolated chronic AR had AVR between 1982 and 2002 according to predefined protocol. Patients were divided into 2 groups depending on their clinical situation at the time of surgery. Group A ("early" surgery) included asymptomatic patients and those in NYHA functional class II with "moderate degrees" of LV dysfunction (LVEFs between and 45% and 50% and/or end-systolic diameters between 50 mm and 55 mm). Group B ("too late" surgery) included patients with either severe symptoms (NYHA functional classes III and IV) or in NYHA functional class I/II with an LVEF <45% or an LV end-systolic diameter >55 mm (21).
One hundred seventy patients were age 50 ± 14 years those >45 years had normal coronary angiograms. Follow-up was 10 ± 6 years (1 to 22 years). Survival up to 22 years was significantly better in Group A patients. Both groups showed significant increases in LVEF, reductions in LV end-diastolic diameter and LV end-systolic diameter, and improvement in NYHA functional class (Table 3). The authors concluded: "Early operation as defined in the guidelines improves long-term survival in patients with chronic AR."
Comment.
A clinically valuable study with the longest documented follow-up data. It started many years before any "guidelines" and thus is a prospective study with patients having had care delivered by a single cardiologist (P.T.) who is a highly experienced and well known cardiologist. When patients were analyzed only by NYHA functional class, the findings were similar to what was previously well known with regard to NYHA and LV systolic function (22,23). Labeling Group B as "too late" is potentially misleading because they also had benefit in NYHA functional class, LV dimensions, and LVEF. It would be more appropriate to label them as "later" surgery.
Randomized trial of vasodilators ("Barcelona trial").
Ninety-five asymptomatic patients with normal LV function were randomized in an open-label trial of angiotensin-converting enzyme inhibitor, nifedipine, or placebo (24). After a mean follow-up of 7 years, there was no statistically significant outcome difference between the 3 groups.
Comment.
There are several concerns with this trial (25): 1) the mean (±SD) of diastolic blood pressure in the nifedipine group was 78 ± 11 mm Hg. In patients with chronic severe AR, this measure is very much lower, which suggests that most patients in the nifedipine group did not have severe AR. Moreover, the LV end-diastolic volume index was 94 ± 27 ml/m2, whereas in the Padua trial it was 126 ± 16 ml/m2 (26), which supports that many patients in the Barcelona trial did not have chronic severe AR; 2) there were 32 patients in the nifedipine arm, 7 (22%) dropped out at 2 ± 7 months, thus, only a small number of patients were randomized. In the Padua trial there were 69 patients in the nifedipine group and 4 were lost to follow-up; and 3) there was no change in blood pressure in the Barcelona trial in which nifedipine 20 mg twice a day was given. In the Padua trial, long-acting nifedipine 20 mg was given twice a day, and at the end of the trial there were significant reductions of LV volumes and increase of LVEF; in the Barcelona trial there were no significant changes in LV volumes or in LVEF.
Surgery in Takayasu Arteritis.
Sixty-three of 90 (70%) patients had AVR (Group A) and 27 (30%) had composite graft repair (Group B). The aortic root diameters in Groups A and B were 39.9 ± 9.5 mm and 54.4 ± 13.6 mm, respectively, p < 0.001 (27). Survival rate at 15 years was 76.1%.
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Bicuspid AV
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Valve preservation and repair for AR.
Aortic valve repair was performed for bicuspid AV + AR in 71 patients, age 41.5 ± 13.2 years (28). Additional procedures were performed in many patients. Four patients were reoperated for recurrent AR. There were no operative deaths and 1 perioperative stroke. At 8 years, the survival was 96.7%, and the incidence of 3 + AR at 8 years was 55.8 ± 10%.
Comment.
The high rate of severe AR at 8 years is of concern.
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Mitral Stenosis
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Long-term results of catheter balloon commissurotomy.
A total of 493 patients, age 31 ± 11 years, were followed for 0.5 to 15 years. At 5, 10, and 13 years, restenosis rates were 1 ± 1%, 32 ± 3%, and 49 ± 6% and event-free survival rates were 92 ± 1%, 80 ± 3%, and 74 ± 3%, respectively. Mitral valve echocardiographic score >8 (p = 0.0003) and age (p = 0.004) were predictors of event-free survival (29).
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MR: MV Prolapse (MVP), Flail Leaflet (F-L)
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Third chromosomal locus for MVP.
Genotypic analyses showed evidence of linkage on chromosome 13q 31.3-32.1q with peak parametric linkage score of 18.41 (p < 0.0007) (30). Multipoint parametric analysis gave a logarithm odd score of 3.17 at marker D13S132. Of 6 related individuals with MV, morphologies not meeting diagnostic criteria but resembling fully developed forms, 5 carried all or part of the haplotype linked to MVP.
Imaging planes to assess localization of MVP or F-L.
In patients with MVP/F-L, transthoracic echocardiography (TTE) was accurate with surgical findings in 91% (Kappa 0.81) and 93% for transesophageal echocardiography (TEE). Mitral valve replacement (MVR) predicted by TTE was an independent predictor for postoperative mortality with OR 5.7; 95% CI 1.97 to 16.4, p = 0.001 (31).
Optimal timing of MV repair (MVrep): the Vienna Study.
One hundred thirty-two consecutive patients, 74 had MVP, 58 had F-L, were prospectively followed for 62 months (32). Patients were referred for surgery: 1) at onset of symptoms; or 2) asymptomatic but developed 1 or more of LV end-systolic diameter 45 mm or 26 mm/m2, fractional shortening = 26 mm/m2, LVEF <0.60, systolic pulmonary artery pressure >50 mm Hg, or recurrent AF. Follow-up was 98% complete, median was 69.2 months. There were 8 deaths (3 in patients with F-L and 5 with MVP); 1 patient who had refused surgery, 1 while still asymptomatic, 1 of myocarditis, 1 of stroke, 2 of cancer, and 2 postoperative. Survival (Table 4) and event-free survival are shown in Figures 7A and 7B. Of 35 patients who had surgery, 23 (82.9%) had MVrep; 23 were asymptomatic, 12 had mild symptoms.
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Figure 7 Actuarial Event-Free Survival in Asymptomatic Patients With Severe Mitral Valve Regurgitation
(A) Kaplan-Meier event-free survival for asymptomatic patients with mitral valve prolapse; (n = 74) versus flail leaflet (n = 58), p = 0.23. (B) Kaplan-Meier survival free of various events. From Rosenchek et al. (32).
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Comment.
A very important study. It documents very good patient outcomes up to 8 years in asymptomatic patients with degenerative severe MR if MVrep is performed: 1) with the development of even mild symptoms during close clinical follow-up; and 2) with the appearance of predetermined objective criteria. Performing MVR in the asymptomatic patient is of some concern.
Surgical MVrep.
Alfieri and his group (33) reported results with edge-to-edge repair in 851 patients with severe MR with anterior leaflet MVP (Alfieri procedure), quadrangular resection of posterior leaflet (PL) MVP; all had concomitant annuloplasty procedure (Table 5) performed from 1991 to April 2004 (Fig. 8). Three patients need reoperation in the anterior leaflet group because of 3+/4+ MR.
Comment.
This was a comparatively younger age group; at baseline about one-third were asymptomatic and about one-third had mild symptoms. Follow-up echocardiogram in PL group was available in 172 of 605 (28.5%).
David et al. (34) reported 701 patients had MVrep for MVP. Ninety-two (13%) age 53.3 years had AL prolapse, 359 (51%) age 60.4 years had PL prolapse, and 250 (36%) age 56.4 years had bileaflet prolapse. Preoperatively, 14.7% and 32.8% were in NYHA functional class I and class II. The operative mortality was 0.01% (5 of 701). Five-year survival was 75 ± 3%. At 12 years, the recurrence rate of 3+ or 4+ MR was 27 ± 3%; it was lowest in those with PL prolapse (Fig. 9). Note that the severity of preoperative MR was not reported.
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Figure 9 Freedom From Recurrent Moderate or Severe MR in Patients with PL, AL, and BL Prolapse
AL = anterior leaflet prolapse; BL = bileaflet prolapse; MR = mitral regurgitation; PL = posterior leaflet prolapse. From David et al. (34).
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Comment.
These 2 studies in patients with MVP document the recurrence rate of 3+ or 4+ MR after MVrep is low on long-term follow-up, and the available data show good patient outcomes were much better and have implications for percutaneous procedures (see the following text). These data also suggest that aggressive treatment with MVrep (in centers with experience and skill for MVrep) is appropriate in patients who fulfill the criteria used in the Vienna study (see the preceding text).
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MR: Ischemic
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MV in end-stage heart failure are not normal.
Mitral valve leaflets and chordae from transplant recipient hearts (11 with dilated and 12 with ischemic cardiomyopathy) were mechanically tested (35). Radially oriented anterior MV leaflets were on average 61% stiffer and 23% less viscous than those from autopsy control hearts. The stiffness of circumferentially oriented anterior MV leaflets was also 50% higher. Leaflet extensibility was reduced by 35%, and failing chordae were 16% stiffer. The p value for all was 0.05.
Comment.
Changes described complement the previous study of the authors that documented biochemical and structural derangements in the extracellular matrix of such valves (36).
Exercise-induced increase in effective regurgitant orifice (ERO) (13 mm) is predictor of worse outcome.
A total of 161 patients with at least mild MR were followed for 35 ± 11 months; of whom, 20 underwent surgery. Of the remaining 141 patients treated medically, 23 died, 22 required hospitalization for heart failure, 4 had non-fatal myocardial infarction, and 11 developed unstable angina (37). By multivariate analysis, an exercise-induced increase of ERO 13 mm2 and a greater increase in transtricuspid pressure gradient were predictors of mortality and of hospital admission for heart failure. An ERO 20 mm2 at rest was an independent predictor of only cardiac death. For all 161 patients, besides ERO, greater increase of LV volumes at rest and a decrease or small increase of LVEF were also predictors of poor outcome.
Beneficial effects of autologous skeletal myoblasts transplantation.
Two months postmyocardial infarction, sheep were randomized to culture medium only (n = 7) or autologous skeletal myoblasts (n = 6) (38). At sacrifice, transplanted animals showed beneficial effects (Table 6).
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Tricuspid Valve
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Tricuspid valve replacement (TVR).
Tricuspid valve replacement was performed in 138 patients (103 mechanical, 35 bioprosthetic valves) (39). Tricuspid valve replacement was isolated in 41. In-hospital and late deaths were 17.6% and 10.4%, respectively. At 15 years, survival was 73.8 ± 8.5%, freedom from reoperation was 66.3 ± 9.4%, and freedom from valve-related events was 49.9 ± 8%. The linearized incidence of valve thrombosis was 1.92% per patient year with mechanical valve.
Tricuspid valve replacement was performed in 81 patients between 1985 and 1999, isolated in 25. Mean age was 61 years, NYHA functional class III to IV in 90%, urgent/emergent in 76%. Tricuspid regurgitation was functional in 22%, organic in 64%, and failed valve repair 14% (40). Operative mortality was 22%. Survival at 5 and 10 years was 60% and 45% for bioprosthesis and 69% and 59% with mechanical valves.
Comment.
Even 46 years after start of valve replacement, the results of TVR are not as good as after AVR or even MVR; operative mortality is higher, and late survival is worse. After TVR comparison of outcomes between the 2 types of valves showed the incidence of thrombosis of mechanical valves is higher and the rate of structural valve deterioration (SVD) of bioprosthesis is higher. Better valves, valve repair techniques, criteria to select patients for surgery, and timing of surgery are needed. Is there a role for percutaneous valve implantation (please see the following text)?
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Infective Endocarditis (IE)
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Prevalence.
From 1970 to 2000, the prevalence of age and gender-adjusted IE ranged from 5.0 to 7.0 cases per 100,000, which did not change significantly over time (p = 0.42 for trend) in residents of Olmstead County, Minnesota (41). Streptococcus viridians was the most common infecting organism (1.7 to 3.5 cases/100,000) and that due to Staphylococcus aureus was the next most common (1.0 to 2.2 cases/100,000). There was a trend of increasing IE in people with MVP (p = 0.04).
Prognostic value of echocardiography.
Four centers prospectively identified 384 consecutive patients with IE, all of whom had TTE and TEE echocardiographic studies from 1993 to 2003 (42). Embolism events (EE) occurred in 131 patients (34.1%) of whom 28 (7.3%) had an embolus after initiation of antibiotic therapy (new embolism events). S. aureus and Streptococcus bovis were independently associated with embolism events whereas vegetation length >10 mm and "severe" vegetation mobility were predictors of new embolism events even after adjustment for S. aureus and S. bovis. One-year mortality was 20.6%. In multivariate analysis, vegetation length >15 mm was a predictor of 1-year mortality (adjusted relative risk 1.8, p = 0.02) independent of other predictors of death and of co-morbidity.
Better outcomes after MVrep.
Thirty-four IE patients, age 51.5 ± 17 years, Euro score 9.8 ± 4.2 had MVrep and 34 patients, age 53.2 ± 13.1 years, Euro score 9.7 ± 3.8 had MVR (43). Mitral valve repair versus MVR operative mortality was the same (11.8%) whereas event-free survival at 5 years was 80.4% versus 54.6%, p = 0.015. By multivariate analysis, patients who had MVrep had better 5-year survival (hazard ratio 0.33, p = 0.02).
Better outcome with surgery for prosthetic valve endocarditis (PVE).
Early PVE (n = 20) and late PVE (n = 84) were associated with an in-hospital mortality of 30% and 19%, respectively (44) (p = 0.43) and a later mortality of 30% and 19%, respectively (p = 0.07). Surgical therapy was associated with a better survival in 2 subgroups: 1) in 25 patients with staphylococcal PVE, in-hospital mortality was lower with surgery 27% versus 73% for medical therapy alone, p = 0.03, and also lower at late follow-up, p = 0.03; and 2) in 69 patients with complicated PVE, in-hospital mortality was lower with surgery 18% versus 48% for medical therapy, p = 0.05, and also lower at late follow-up, p = 0.001.
Comment.
Figures show almost all the benefit of better survival was due to lower in-hospital mortality.
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European Society of Cardiology Recommendations
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The European Society of Cardiology recommendations relate to management of patients after heart valve surgery (45); competitive sports participation in athletes with cardiovascular disease (46).
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"Newer" Interventional Therapeutic Procedures
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Off-pump surgical MV implantation.
Off-pump, transatrial mitral valve implantation with stented Medtronic (Minneapolis, Minnesota) Mosaic bioprosthesis through an opening in the atrial wall attempted in 6 sheep was successful in 5 (47). Left atrial and LV end-diastolic pressures were elevated. Left ventricular angiogram showed no MR (Fig. 10). The animal with the better hemodynamics was kept alive and was still alive 3 months after implantation.
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Figure 10 Angiograms After Transatrial Insertion of Collapsible Valve Stent
(A) Aortogram showed no aortic regurgitation. (B) Left ventriculogram showed no mitral regurgitation and no evidence of subaortic stenosis. From Boudjemline et al. (47).
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Comment.
An interesting development by Bonhoeffer who was the first with percutaneous valve implantation pulmonary in 2000 (48). Mitral valve implantation is not percutaneous yet. Tricuspid percutaneous prosthetic heart valve (PHV) might be the next step because percutaneously it is more easily accessible than the mitral and the results of surgical TVR are still not as good as after surgical AVR or MVR (see the preceding text).
Pulmonary percutaneous valve implantation.
Pulmonary percutaneous valve implantation was successful in 58 of 59 patients, median age 16 years, median weight 56 kg after repair of congenital heart disease (48). There were significant reductions of right ventricular (RV) pressure, RV outflow tract gradients, pulmonary regurgitation, regurgitant fraction, and RV end-diastolic volume and increases of LV end-diastolic volumes, RV stroke volume, and of maximum VO
2 on exercise.
Transapical AV implantation.
An emaciated, 52 kg, 75-year-old woman in congestive heart failure had calcific AS with 54 mm Hg mean gradient, AVA 0.4 cm2 and LVEF 0.35 (49). At surgery, with portable C-arm providing fluoroscopy and anterolateral thoracotomy, the heart was exposed and pericardium opened. A stiff 24-F valve delivery sheath was introduced into the LV and the Cribier valve (Edwards Lifesciences, Irvine, California) was implanted in the AV. The patient was well and able to walk on the third postoperative day and discharged home on the ninth day. At 1 month, AVA was 1.7 cm2; at 2 months patient was not in heart failure.
Percutaneous retrograde AV implantation.
Percutaneous AV implantation was attempted in 18 patients (age 81 ± 6 years) in whom surgical risk was deemed excessive. After successful percutaneous valve implantation with the Cribier valve (Edward Lifesciences) in 14 patients, which was approved for compassionate clinical use, AVA increased from 0.6 ± 0.2 to 1.6 ± 0.4 cm2. At follow-up of 75 ± 55 days, 16 of 18 patients (89%) were alive (50).
AV implantation for calcific AS: "mid-term" follow-up.
This is an additional report of the "initial feasibility studies." Eleven of 27 patients were alive at follow-up ranging from 9 months (n = 2) to 26 months (n = 2). All patients experienced amelioration of symptoms (>90% in NYHA functional class I/II) (51). PHV remained unchanged during follow-up, and "no deaths were device related."
Comment.
A multicenter study that included this group reported 3+ or 4+ AR in 21 of 41 (51%) patients who had received the 23-mm PHV and 0 of 4 patients with 26-mm PHV (52).
Percutaneous MVrep using edge-to-edge technique.
Twenty-seven patients had a 6-month follow-up in the Food and Drug Administration-approved phase I safety and feasibility trial (EVEREST) (53). Patients had moderate-to-severe or severe MR, and all patients were candidates for MV surgery in the event that it was required for managing potential complications. Patients were selected if they met basic criteria for intervention according to guideline recommendations. Ninety-three percent had "degenerative" and 7 ischemic etiology for the MR. A total of 85% (23 of 27) were free of major adverse event at 30 days; the 4 major events were permanent stroke in 1 and clip detachment from 1 leaflet in 3. At 1 month, MR was 2+ in 14, and 13 of 14 maintained that MR at 6 months. Three patients with partial clip detachment and another patient with unresolved MR underwent MV surgery; among patients discharged from the hospital with a clip in place, freedom from valve surgery at 6 months was 18 of 22 (82%).
Percutaneous transvenous mitral annuloplasty.
Five patients, age 67 ± 10 years underwent transvenous mitral annuloplasty with the Edwards system which was successful in 4 (54). There was one late death at day 148. Values at baseline and at 3 months for mitral annular diameter were 36 ± 3 mm and was 35 ± 1 mm; LVEFs were 42 ± 11% and 50 ± 6%; NYHA functional classes were 2.4 ± 0.5 and 2.0 ± 0.7. Baseline MR grade was 3.0 ± 0.7 and was grade 1.6 ± 1.1 at the last postprocedural visit.
Percutaneous septal sinus shortening.
New percutaneous procedure was developed that allows for shortening of the septal-to-lateral (SL) mitral annular diameter. Sheep underwent rapid RV pacing to obtain moderate-to-severe functional MR (55). Postimplantation SL diameter decreased in 19 sheep from 32.5 ± 3.5 to 24.6 ± 2.4 mm, p < 0.001, and MR was reduced from 2.1 ± 0.6 to 0.2 ± 0.4, p < 0.001. At 30 days, in 4 animals, SL diameter had decreased from 30.4 ± 1.9 to 23.9 ± 0.5, p = 0.01, MR was decreased from 1.8 ± 0.5 to 0.2 ± 0.1, p = 0.01, and mean pulmonary artery wedge pressure was reduced from 23.9 ± 4.1 to 13.8 ± 2.2 mm Hg (p = 0.01).
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Prosthetic Heart Valves
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Very impressive long-term results of mechanical MVR in young women.
Two-hundred sixty seven patients, age about 31 ± 7 years, received caged ball (n = 73), tilting disc (n = 133), or bileaflet (n = 61) PHV. The international normalized ratio (INR) was 3.0 to 4.0 with caged ball and with tilting disc (79.4% of those with caged ball also received aspirin 100 mg/day) and was 2.5 to 3.5 with bileaflet PHV (56). Thirty-day mortality was 1.1%. Twenty-five-year results are shown in Table 7. Atrial fibrillation was an independent risk factor for mortality, and LVEF was protective for mortality. Atrial fibrillation and carbomedics valve were predictors for thromo-emboli, and tilting disc was a predictor of reoperation. At end of study, 208 of 267 (78%) were still alive; 61.1% and 33.6% were in NYHA functional class I and II, respectively.
When receiving warfarin therapy, 35 patients undertook 46 pregnancies and none (0) experienced adverse cardiac- or valve-related events. There were 27 healthy babies, 16 spontaneous abortions, 2 stillbirths, and 1 had ventricular septal defect. Fetal events were less frequent with a daily warfarin dose <5 mg (p < 0.001). Two patients treated with heparin after "general practitioner counseling" experienced valve thrombosis necessitating surgery and had perioperative abortion. With regard to warfarin-treated subset, INR was estimated weekly, no patient experienced adverse cardiac- or valve-related events during child bearing.
Randomized trials of PHV hemodynamics.
There was no significant difference in 16 patients at 3 to 6 months and at 1-year in AVA index (cm2/m2) between the Toronto stentless (St. Jude Medical, St. Paul, Minnesota) porcine valve and the PERIMOUNT stented bovine pericardial valve (Edwards Lifesciences) (Table 8) (57). At 1 year, there was a decrease in LV mass index (g/m2) of 11% from 224 to 177 g/m2 in the Toronto stentless and of 20% from 249 to 182 g/m2 for the PERIMOUNT (p = 0.21).
At hospital discharge, the AVA index (cm2/m2) of the Carpentier-Edwards PERIMOUNT Magna 1.07 ± 0.4 was greater than that of the Carpentier-Edwards PERIMOUNT (0.80 ± 0.2) or the Edward Prima Plus (Edwards Lifesciences) (0.87 ± 0.3) (p = 0.028) (58).
Comment.
Other randomized trials of PHV areas between the PERIMOUNT and Toronto Stentless and the PERIMOUNT (Edwards Lifesciences) and Medtronic Mosaic were described earlier (2,59).
Higher late mortality with severe valve prosthesis-patient mismatch (VP-PM).
Three hundred eighty-eight patients, age 62 ± 13 years, had AVR with a 19- or 21-mm St. Jude Medical prosthesis from 1985 to 2000. PHV index was calculated from the first postoperative TTE within 1 year (60). Patients with severe VP-PM (AVA index 0.6 cm2/m2, n = 66) had a significantly higher body surface area 1.91 ± 0.22 m2 than those with moderate VP-PM, p < 0.0001. Patients with severe VP-PM had a lower 5-year survival (72 ± 6%) and 8-year survival (41 ± 8%) than those with moderate VP-PM (80 ± 3% and 65 ± 5%, p = 0.026) or mild VP-PM (85 ± 3% and 74 ± 5%, p = 0.002). This was true in those with 19- or 21-mm PHV. The 8-year incidence of congestive heart failure was significantly (p = 0.02) higher in those with severe (29 ± 8%) than with moderate (14 ± 3%) or mild (13 ± 4%) VP-PM.
Comment.
The number of patients who had their first postoperative TTE in-hospital and at 6 and 12 months would be important to know.
SVD of biological valves with follow-up 15 years.
Four hundred seventy-eight patients, age 65 ± 11 years, 138 were <60 years, received Carpentier-Edwards pericardial valves (PERIMOUNT, Edwards Lifesciences) and were followed-up for 15 ± 5.1 years (61). Structural valve deterioration for pericardial valves at 15 years and 19 years was 23% and 53%. Explantation for SVD in the pericardial valves was low in those age >60 years.
Comment.
Younger patients, especially age 50 years, had a much higher rate of SVD. Explantation for SVD is likely to be lower than rate of SVD.
A total of 1,464 patients received the Mitroflow synergy bovine pericardial valve (BC MedTech, Vancouver, Canada). Structural valve deterioration at 5, 10, and 15 years was 1.0 ± 0.3%, 17.2 ± 2.2%, and 37.2 ± 5.8%, respectively (62).
Comment.
Structural valve deterioration began at about 5 years, and then increased very rapidly particularly in those age <70 and 70 to 74 years. There were few patients at risk at 15 years.
A total of 1,599 patients, age 67 ± 11 years, had PHV with Hancock II bioprosthesis (Medtronic) (AVR in 1,010 patients and MVR in 559 patients) (63). After AVR, the rate of SVD in those age <65 years versus those 65 years at 10 years was 6 ± 2% versus 1 ± 1%, respectively, and at 20 years was 61 ± 9% versus 27 ± 16%, respectively. After MVR, the rate of SVD in those age <65 years versus those 65 years at 10 years was 18 ± 5% versus 5 ± 2% and at 20 years was 73 ± 9% versus 41 ± 11%.
Comment.
Structural valve deterioration was defined as "clinically relevant valvular stenosis or insufficiency as determined by Doppler echocardiography, reoperation, or autopsy." The number of patients and number of the echocardiography/Doppler studies performed over time are not described.
Other issues.
Very high rate of bleeding with mechanical PHV in elderly people
A total of 392 patients, mean age 74 years, had AVR with stentless freestyle bioprosthesis (n = 247) or mechanical St. Jude prosthesis (n = 145). Mean follow-up was 30 ± 18 months (64). There were no statistical differences in outcomes between the 2 types of PHV. Patients >75 years with mechanical valve had a greatly increased risk of major bleeding events (OR 18.9, 95% CI 2.2 to 163.0, p = 0.007) and patients receiving "coumarin" had a 2-fold increased risk of an impaired emotional reaction (p = 0.052).
Reoperation for aortic aneurysm after Ross principle
Of 112 patients, 29 ± 10 years of age, 110 had follow-up 5.1 ± 1.9 years (range 0.3 to 10.6 years). At 10 years, the incidence of aortic dilatation (diameter >4 cm/0.21 cm/m2) was 29%; aortic aneurysm (>5.0 cm) was 6%. At 10 years, the incidence of reoperation was 19 ± 6%, of valve replacement 12 ± 5%, and of any reintervention 28 ± 10% (65).
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Miscellaneous
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Normal Valves: Development and...
Familial Aggregation of Calcific...
