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REVIEW




Valvular Heart Disease: A Century of Progress
Sanjay Sharma, MD, Anilkumar Mehra, MD, Shahbudin H. Rahimtoola, MB, FRCP, DSc (Hon)
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, Calif.



                   ABSTRACT

                  The 20th century witnessed amazing advances in the diagnosis and treatment of valvular heart disease. The
                  advances and our hopes for future progress are described.
                  © 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, 664-673

                   KEYWORDS: Cardiac catheterization; Doppler echocardiography; Percutaneous catheter intervention; Valve surgery


“How can you understand the world if you don’t know what                     the Medical Research Council, he advocated prospective
happened in it?”                                                             follow-up studies, or “after-histories,” of patients. These
                               —John W. Kirklin, MD1                         after-histories5 were the predecessors of databases and reg-
   Since the turn of the 20th century, extraordinary ad-                     istries in use today.
vances have been made in the diagnosis and treatment of                          According to Feinstein,6 the first randomized controlled
valvular heart disease. Some of the major achievements                       study in scientific literature was reported in agricultural
underlying these advances have received due recognition                      experiments carried out by T. Eden in 1923 on the effect of
(Table 1).2 Breakthroughs in medicine are a culmination of                   manure on potato crops. The first randomized clinical trial
small advances3 in valvular heart disease. Different small                   in valvular heart disease began in 1954.7 The 5-year results
advances occurred in both halves of the century (Tables                      are shown in Table 4.8
2 and 3).
                                                                             Rheumatic Fever and Carditis
THE FIRST HALF OF THE LAST CENTURY                                           In the first half of the 20th century, rheumatic heart disease
                                                                             was a major problem; for example, in Britain, rheumatic
Setting the Stage                                                            heart disease accounted for 20% of all heart disease and
During World War I, Lewis,4 charged with the care of                         10,000 deaths annually.9
combatants with heart disease, noted the inadequate under-                      The observations that led to the conquering of this
standing of cardiac disease and its prognosis. In a report to                scourge merit a brief review.10 From an epidemiologic sur-
                                                                             vey, Newsholme11 correctly deduced that an active infective
    Dr Rahimtoola has received honoraria for educational lectures from the   agent and conditions of environmental and personal factors
American College of Cardiology Foundation (Washington, DC); American         were required for the development of rheumatic fever.
College of Physicians (Philadelphia, Pa); University of California Los
                                                                             Aschoff described the specific rheumatic lesion (Aschoff
Angeles; University of California Irvine; Cornell University (New York,
NY); Creighton University (Omaha, Neb); Thomas Jefferson University          body).10 In the late 1920s, Griffith and Lancefield identified
(Philadelphia, Pa); Cedars-Sinai Medical Center (Los Angeles, Calif);        Group A hemolytic streptococcus as the causative organ-
Harvard Medical School (Boston, Mass); University of Wisconsin (Mil-         ism.10 Centers were established in New York, Boston, and
waukee Campus, Wis); University of Hawaii (Honolulu, Hawaii); Cardi-
                                                                             London for the long-term care of these patients. In 1944,
ologists Association of Hong Kong, China; ATS (New York, NY); St Jude
Medical (St Paul, Minn); Carbomedics (Austin, Tex); Merck (Whitehouse        Jones12 published his seminal work on the diagnosis of rheu-
Station, NJ); Pfizer (New York, NY); and Edwards Life Sciences (Irvine,       matic fever. In Denmark, improvements in socioeconomic
Calif).                                                                      conditions and housing dramatically reduced the incidence
    Requests for reprints should be addressed to Shahbudin H. Rahimtoola,
                                                                             of rheumatic fever before the antibiotic era (Figure 1).10
MD, University of Southern California, 2025 Zonal Avenue, GNH 7131,
Los Angeles, CA 90033.                                                       Rheumatic carditis and valve disease have been virtually
    E-mail address: rahimtoo@usc.edu                                         eliminated from developed countries, similar to the virtual

0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2008.03.027
Sharma et al    Valve Disease                                                                                                 665

elimination of smallpox and poliomyelitis in the world by           Coronary Arteriography. Sones and colleagues22 obtained
vaccines.                                                           a selective coronary arteriogram by inadvertently engaging
                                                                    the right coronary artery during an aortogram. Subse-
                                                                    quently, coronary arteriography became routine in clinical
THE SECOND HALF OF THE TWENTIETH CENTURY                            practice but required arterial cutdown. The development of
Patient Assessment                                                                            a percutaneous arterial access
Pressure Measurement. Efforts                                                                 technique by Seldinger16 and of
to quantify the severity of valvular                                                          preformed catheters by Judkins23
                                          CLINICAL SIGNIFICANCE
heart disease began in 1945 with                                                              made coronary arteriography fea-
attempts to measure intracardiac          ● The diagnosis and assessment of the se-           sible for widespread use. The data
pressures. In landmark studies,             verity of valve stenosis and regurgitation        obtained by catheterization, ven-
               13
Hellems et al and Lagerlöf and              are at an advanced level of accuracy.             tricular and aortic angiography,
       14
Werkö documented that pres-                                                                   and selective coronary arteriogra-
                                          ● Interventional therapy in patients with           phy are the foundation for evalu-
sures recorded with a cardiac cathe-
ter wedged into the distal pulmonary        valvular heart disease results in an im-          ation of valvular heart disease.
artery reflected left atrial pressure.       provement of symptoms, functional class,
Ross15 developed the transseptal            left ventricular function, and pulmonary          Doppler Echocardiography and
approach to the left ventricle. Per-        hypertension. Survival is improved in             Ultrasonography. Edler and
cutaneous transthoracic puncture            many patients.                                    Hertz,24 using ultrasonography,
of the left ventricle was used to                                                             first recorded the movement of
                                          ● All patients should be considered poten-          cardiac structures in 1953. Early
measure left ventricular pressure in
aortic stenosis. Subsequently, the          tial candidates for interventional therapy        M-mode echocardiography was
Seldinger16 technique for percuta-          and should undergo appropriate clinical           effective in the diagnosis of mitral
neous entry into a systemic artery          evaluation and diagnostic testing.                stenosis; 2-dimensional echocar-
revolutionized retrograde access                                                              diography allowed for real-time
to the ascending aorta and left                                                               visual morphologic evaluation of
ventricle.                                                                                    cardiac structure and function. Su-
                                                                    perimposition of Doppler by Hatle and colleagues25 allowed
Valve Area Calculations. By comparing hydraulic systems             for indirect hemodynamic measurement. Transesophageal
and cardiac physiology, Gorlin and Gorlin17 derived the             echocardiography increased the clarity and accuracy of a
following formula for calculating mitral and aortic valve           number of valvular heart diseases.
areas:                                                                 Echocardiography/Doppler permitted the rapid initial as-
                                                                    sessment of patients with mild, moderate, or severe valvular
                                  CO/HR       DFP
           mitral valve area                                        heart disease. It also was of great value not only in diag-
                                  37'.9'   gradient                 nosing unsuspected lesions but also in excluding disease.
                                                                    Along with the chest x-ray and the electrocardiogram, echo-
                                   CO/HR       SEP'                 cardiography/Doppler has become an essential component
           aortic valve area
                                 44'.3'    gradient'                of the clinical evaluation of patients with valvular heart
                                                                    disease. Computed tomography, electron beam computed
where CO         cardiac output, HR       heart rate, DFP           tomography, and cardiac magnetic resonance imaging have
diastolic filling period, and SEP systolic ejection period.          not been proven superior to echocardiography/Doppler for
                                                                    this purpose.
Angiography. The first angiocardiogram in humans was
                                              18
performed by Castellanos and colleagues. Aortography
and left ventricular angiography were essential to assessing        INDIVIDUAL LESIONS
aortic and mitral regurgitation. Dodge and colleagues19 ac-
curately calculated the left ventricular volumes and ejection       Mitral Stenosis
fraction from left ventricular angiograms using Arvidsson’s         In 1954, the outstanding clinical cardiologist and scholar
technique.                                                          Paul Wood26 described the clinical features, pathophysiol-
                                                                    ogy, complications, and outcomes of mitral stenosis. He
Normal Values. Values for right-sided heart pressures, pul-         documented that, on average, the symptoms of mitral ste-
monary artery wedge pressure, and cardiac output were               nosis began 19 years after rheumatic carditis.
documented in healthy volunteers.20 Another study in                   As early as the 1920s, but mainly in the early 1950s,
healthy subjects documented right and left-sided heart pres-        mitral commissurotomy was performed by manual dilata-
sures and left ventricular volumes and ejection fraction.21         tion (“finger fracture”).27 Later in the 1950s, the results
The normal cardiac index was found to be 3.6               0.9      were improved by using the Tubbs’ dilator, which is intro-
L/min/m2.                                                           duced from the left ventricular apex. Both of these proce-
666                                                                       The American Journal of Medicine, Vol 121, No 8, August 2008

dures were “blind” (closed). When performed by a skilled,                      Table 2     Procedural Advances in Valvular Heart Disease
experienced surgeon on an appropriate patient, closed mitral
commissurotomy had an excellent outcome; the survival                         Discoveries by 6 Nobel Laureates who have had an impact on
was better than that of medical therapy (Figure 2),28 and the                       valvular heart disease
24-year survival was 84%.27 The next development was                          Identification of the infecting organism of rheumatic fever
“open” mitral commissurotomy, which incorporated extra-                       Establishment of databases
                                                                              Performance of randomized clinical trials
corporeal circulation. However, in skilled surgical hands,
                                                                              Measurement of intracardiac pressures and calculation of valve
the results of closed and open mitral commissurotomies                              areas
were similar.29 In the early 1960s, mitral valve replacement                  Left ventricular angiography, aortography, coronary
provided excellent results for those patients who were poor                         arteriography
candidates for surgical commissurotomy.30                                     Echocardiography/Doppler
   The 1980s ushered in the era of catheter balloon com-                      Total cardiopulmonary bypass for intracardiac surgery
missurotomy; the double balloon technique was followed by                     Cardiac Surgery:
the Inoue balloon (Toray Medical Co, Ltd), which is still in                     Commissurotomy
current use. In randomized trials, catheter balloon commis-                      Prosthetic heart valves
surotomy yielded outcomes at least as good as those ob-                          Valve repair
tained from closed or open surgical commissurotomy.31                            Robotic surgery
                                                                                 Coronary artery bypass graft surgery
All 3 procedures yield the best results for mobile and
                                                                                 Percutaneous catheter intervention for coronary artery
                                                                                    disease
                                                                                 Catheter balloon commissurotomy
Table 1 Nobel Prize and Lasker Award-winning
Achievements Relevant to Valvular Heart Disease

Wilhelm Conrad Röntgen The Nobel Prize in Physics 1901
                        “In recognition of the extraordinary
                          services he has rendered by the
                          discovery of the remarkable rays                     Table 3     Accomplishments in Valvular Heart Disease
                          subsequently named after him”
Alexis Carrel           The Nobel Prize in Physiology or                      Virtual elimination of rheumatic valve disease in developed
                          Medicine 1912                                           countries
                        “In recognition of his work on                        Reduction of rheumatic fever, rheumatic fever recurrences, and
                          vascular suture and the                                 rheumatic valve disease in developing countries
                          transplantation of blood vessels                    Recognition of drug-induced valve disease
                          and organs”                                         More accurate diagnosis of valve disease and assessment of
Willem Einthoven        The Nobel Prize in Physiology or                          their severity
                          Medicine 1924                                       Significantly better assessment of severity of valve diseases
                        “For his discovery of the mechanism                   Definition of valvular abnormality/pathology
                          of the electrocardiogram”                           Correction of valve abnormality/pathology
Gerhard Domagk          The Nobel Prize in Physiology or                      Relief of mitral stenosis by percutaneous catheter technique
                          Medicine 1939                                       Appropriate selection of valve replacement device and procedure
                        “for the discovery of the antibacterial                   resulting in improvement of symptoms, functional status,
                          effects of prontosil”*                                  left ventricular function, pulmonary hypertension, and
Sir Alexander Fleming,  The Nobel Prize in Physiology or                          survival
Ernst Boris Chain, Sir     Medicine 1945
Howard Walter Florey    “for the discovery of penicillin and its
                           curative effect in various infectious
                           diseases”
André Frédéric          The Nobel Prize in Physiology or
Cournand, Werner           Medicine 1956                                       Table 4     Recurrence of Rheumatic Fever*
Forssmann, Dickinson W. “for their discoveries concerning
Richards                   heart catheterization and                                                                         Per          Compliance
                           pathological changes in the                                                                       Year, %      Rate, %
                           circulatory system”                                Benzathine penicillin, 1.2 million             0.4          94
Albert Starr, Alain     Albert Lasker Clinical Research Award                    (intramuscular) every 4 wk
Carpentier                2007                                                Oral penicillin G, 200,000 U once daily        5.5          50
                        “Surgeon-scientists who                               Sulfadiazine, 1 g/d                            2.8          50
                          revolutionized the treatment of
                                                                                   *Data from Alban B, Epstein JA, Feinstein AR. Rheumatic fever in
                          heart disease”
                                                                               children and adolescents: a long-term epidemiologic study of subsequent
   *Protonsil was the first synthetic drug used for treatment of general        prophylaxis, streptococcal infection and clinical sequelae. Ann Intern
bacterial infections in humans.                                                Med. 1964;60(Suppl 5):1-129.
Sharma et al                            Valve Disease                                                                                                      667

                                                                                                matic fever and carditis: On average, symptoms of aortic re-
         Reported Rheumatic Fever, Denmark, 1862-1962                                           gurgitation began 20 years after the occurrence of carditis.
                          300                                                                   The incidence of death, angina, or heart failure was 87% at
                          200
                                                                                                6 years in the high-risk group and 8% at 15 years in the
                                                                                                low-risk group.32 In the current era, aortic regurgitation is
  MORBIDITY PER 100,000




                                                                             Penicillin         usually the result of aortic root dilation with echocardiog-
                          100
                                                                                                raphy/Doppler used to study the natural history.31 Of
                                                                                                asymptomatic patients with normal left ventricular ejection
                           50
                                                                                                fraction, approximately 3% to 6% per year become symptom-
                                                                                                atic or progress to left ventricular dysfunction; more than one
                                                                                                quarter of patients with left ventricular dysfunction become
                           20
                                                                                                symptomatic per year; and the mortality for symptomatic
                                                                                                patients is more than 10% per year. In addition, echocar-
                           10
                             1860 ‘70   ‘80   ‘90 1900 ‘10 ‘20   ‘30   ‘40   ‘50   ‘60    ‘70   diographic data for left ventricular dimensions show that an
                                                      YEAR
                                                                                                end-diastolic dimension of 70 mm ( 35 mm/m2) or an
                                                                                                end-systolic dimension of 50 mm ( 25 mm/m2) increases
 Figure 1 Incidence of rheumatic fever in Denmark from 1862
 to 1962. From the Public Health Board of Denmark, Copenha-                                     the chance that a patient will become symptomatic or de-
 gen, Denmark. This is a log scale; from 1860 to 1945 morbidity                                 velop left ventricular dysfunction.31 Left ventricular dys-
 decreased by approximately 75%. The time when penicillin was                                   function precedes the development of symptoms in more
 available for clinical use (arrow). Adapted from Stollerman GH.                                than half of asymptomatic patients.31,33
 Rheumatic Fever and Streptococcal Infections. New York:                                            Arteriolar dilators were shown to have beneficial effects
 Grune & Stratton, Inc. 1975;21-146.                                                            on hemodynamics and left ventricular size during 1 year of
                                                                                                follow-up. These data set the stage for a randomized trial
                                                                                                documenting that long-acting nifedipine reduced or de-
nonthickened or mildly thickened valves. Catheter bal-                                          layed the need for aortic valve replacement in asymp-
loon commissurotomy is now the first-line treatment for                                          tomatic patients with normal left ventricular ejection
mitral stenosis.30                                                                              fraction (Figure 3).33 In all symptomatic patients, aortic
                                                                                                valve replacement was shown to have beneficial effects on
Aortic Regurgitation                                                                            symptoms, as well as left ventricular size and function, even
Most patients described in the after-histories of Lewis4 had                                    when baseline left ventricular systolic function was abnor-
chronic aortic regurgitation. There were 3 eras.32 The era of                                   mal;34 minimally symptomatic and asymptomatic patients
syphilis: The data are largely from the preantibiotic era;                                      with mild left ventricular dysfunction have the best out-
syphilitic cardiovascular disease is now rare. The era of rheu-                                 comes from the procedure.35



                                                         MITRAL STENOSIS                                MITRAL STENOSIS
                                                        (Functional Class II)                        (Functional Class III & IV)




                                               Figure 2 Closed mitral commissurotomy is associated with better survival than medical
                                               therapy in patients with severe mitral stenosis who were mildly symptomatic (left) and
                                               severely symptomatic (right). Adapted from Roy SB, Gopinath N. Mitral stenosis. Circu-
                                               lation. 1968;38(suppl V):68-76.
668                                                                 The American Journal of Medicine, Vol 121, No 8, August 2008

                                                                        occur in older patients. Atherosclerosis and inflammation
                                                                        are important factors in the complex cause of calcific aortic
                                                                        stenosis.36,37 The life expectancy of patients has markedly
                                                                        increased; calcific aortic stenosis is now the most common
                                                                        reason for valve replacement.
                                                                            In 1968, an analysis of autopsy data showed a 3-year
                                                                        average life expectancy for symptomatic patients with se-
                                                                        vere aortic stenosis.38 Twenty years later, a follow-up study
                                                                        after cardiac catheterization confirmed the short life expect-
                                                                        ancy.39 In both studies, life expectancy after the onset of
                                                                        heart failure was only 1 to 2 years.
                                                                            In the 1970s, the importance of correcting aortic valve
                                                                        areas for body size was recognized.40 Severe aortic stenosis
                                                                        was diagnosed as aortic valve areas of 1.0 cm2 or less ( 0.6
                                                                        cm2/m2);41 more recently, severe aortic stenosis was defined
                                                                        as an aortic valve area of 0.7 cm2 or less ( 0.4 cm2/m2). A
 Figure 3 Long-acting nifedipine administered twice daily re-           mean aortic valve gradient of 50 mm Hg or more is usually
 sults in a lower incidence of the need for aortic valve replace-
                                                                        a reliable indicator of severe aortic stenosis.42
 ment in asymptomatic patients with chronic severe aortic regur-
 gitation and normal left ventricular ejection fraction. From               In symptomatic patients with severe aortic stenosis, aor-
 Scognamiglio R, Rahimtoola SH, Fasoli G, et al. Nifedipine in          tic valve replacement has a beneficial effect on symptoms,
 asymptomatic patients with severe aortic regurgitation and nor-        left ventricular function, left ventricular hypertrophy, and
 mal left ventricular function. N Engl J Med. 1994;331:689-695.         survival (Figure 4).39,43 It also markedly improves symp-
 PTS patients; AR aortic regurgitation; LV left ventricular.            toms in patients with severe aortic stenosis and clinical heart
                                                                        failure; if patients have no history of myocardial infarction
                                                                        and the procedure is performed early, the left ventricular
Aortic Stenosis                                                         ejection fraction normalizes in one half to two thirds of
Most cases of severe aortic stenosis currently seen in de-              patients (Figure 5).44 These positive outcomes also occur in
veloped countries are calcific (so-called degenerative) and              patients with aortic stenosis, low aortic valve gradients, and




                                                 operated                                 operated




                                                non-operated

                                                                                           non-operated
                                                                                           non-




                          A                                              B
                        Figure 4 Survival is better after aortic valve replacement (operated) than with medical
                        therapy (non-operated) in patients with severe aortic stenosis. A: Adapted from Schwarz F,
                        Banmann P, Manthey J, et al. The effect of aortic valve replacement on survival. Circu-
                        lation. 1982;66:1105-1110. B: Adapted from Horstkotte D, Loogen F. The natural history
                        of aortic valve stenosis. Eur Heart J. 1988;9(suppl E):57-64.
Sharma et al                  Valve Disease                                                                                    669

                                                                      a complication of the dilated orifice and diseased valve. The
                                                                      subsequent results depend on the degree of the exhaustion
  AVR FOR AS IN HEART FAILURE                                         of the muscle of the heart. The backward pressure resulting
                        1.0                                           from the regurgitation embarrasses the left auricle, pulmo-
                                                                      nary circulation, and right heart.” These observations, made
                                                                      in 1908, are valid even now.
                        0.9         mean ± SE                            The incidence of mitral regurgitation in patients with
                                                                      rheumatic valve disease was documented to be 34%.9 In
                        0.8                                           the late 1950s, ruptured chordae tendineae were recog-
                                                                      nized as the cause of acute mitral regurgitation. At the
    EJECTION FRACTION




                        0.7                                           1958 Goulstonian Lecture, Leatham47 gave his classic
                                                                      presentation on auscultation of the heart. However, he
                                                                      thought that late systolic sounds were pericardial/pleural
                        0.6
                                                                      in origin and that the accompanying murmur was
                                                                      “innocent” (Figure 16 in his article).47 Also in 1958,
                        0.5
                                                                      McKusick48 wrote a treatise on cardiovascular sounds,
                                                                      describing in considerable detail a “musical pleural peri-
                        0.4                                           cardial murmur” often preceded by a click. He noted that
                                                                      this sound had been described earlier, first in 1843 in
                        0.3                                           patients with valves later determined at autopsy to be
                                                                      “normal,” and then in 1880 by Osler.48
                                                                         In 1963, on the basis of autopsy findings, Barlow and
                        0.2
                                                                      colleagues49 described mitral valve prolapse as a cause of
                                                                      these sounds. Subsequently, mitral valve prolapse was
                        0.1                           P<0.001         diagnosed clinically by left ventricular angiography.
                                                                      Echocardiography/Doppler represented a major advance
                         0                                            that not only provided evidence of the causes of mitral
                                  Pre-Op          Post-Op             regurgitation, including mitral valve prolapse, and the
                         Peri-Op MI and late CHB
                                                                      pathophysiologic changes associated with mitral regurgi-
                         Post-Op: Perivalvular Aortic Regurgitation   tation, but also showed that mitral valve prolapse is
                                                                      common and the most common cause of ruptured chordae
 Figure 5 Left ventricular ejection fraction improves and even        tendineae, which became known as “flail leaflets.” Mitral
 normalizes after aortic valve replacement in approximately two       regurgitation also can be caused by coronary artery dis-
 thirds of patients with severe aortic stenosis and clinical heart    ease because of its effect on the left ventricle. Recently,
 failure. Adapted from Smith N, McAnulty JH, Rahimtoola SH.           some drugs also have been shown to cause valvular
 Severe aortic stenosis with impaired left ventricular function       regurgitation.50
 and clinical heart failure. Results of valve replacement. Circu-        Symptomatic patients with severe mitral regurgitation
 lation. 1978;58:255-264. AVR aortic valve replacement; SE
                                                                      benefited from mitral valve replacement or repair. In asymp-
     standard error; MI      myocardial infarction; CHB      com-
 plete heart block.                                                   tomatic patients, mitral valve replacement or repair can be
                                                                      deferred until the onset of symptoms or evidence of left
                                                                      ventricular dysfunction, pulmonary hypertension, or atrial
                                                                      fibrillation.51
severe left ventricular dysfunction if they have severe aortic
stenosis.45                                                           Tricuspid Valve Disease
                                                                      In 1908 Mackenzie46 observed, “Although actual disease
Mitral Regurgitation                                                  of the valves is rare, incompetence of the tricuspid orifice
In the early 1900s, mitral regurgitation was the most                 is extremely common . . . It should never be concluded
commonly diagnosed valve lesion. At that time, physi-                 that no tricuspid regurgitation occurs because of the ab-
cians were strongly discouraged from overdiagnosing                   sence of a murmur . . . A weak muscular wall and wide
organic mitral regurgitation, thus saving healthy subjects            orifice may give rise to no murmur.” These observations
from invalidism.9                                                     remain relevant even today, and good methods for repair-
   Mackenzie46 was well aware of the spectrum of the                  ing or replacing tricuspid valves are still lacking. There is
clinical aspects of mitral regurgitation, writing, “The really        a great need for improvements in surgical techniques,
serious trouble in connexion with mitral regurgitation arises         replacement valves, and assessment of patients for
when the muscle is impaired and the regurgitation is due to           surgery.
670                                                                                The American Journal of Medicine, Vol 121, No 8, August 2008



                                                              Starr-Edwards
                                                              Starr-                                               St. Jude
              100                                                                                    100
                     90                                                                                       90
                     80                                                                                       80




                                                                                      vent-free urvival (%)
                     70                                                                                       70
      Survival (%)




                     60                                                                                       60
                     50                                                                                       50
                     40                                                                                       40




                                                                                         S
                              n=122 n=113 n=104 n=93   n=75   n=59   n=38   n=21                                       n=112 n=101 n=85    n=75   n=55   n=42   n=25   n=12
                     30                                                                                       30
                     20                                                                                       20




                                                                                      E
                              n=118 n=110 n=102 n=90   n=78   n=60   n=44   n=24                                       n=106 n=92   n=83   n=72   n=59   n=45   n=32   n=17
                     10                                                                                       10

                     0                                                                                        0
                          0     1     2    3     4    5     6    7           8                                     0     1     2    3     4    5     6    7              8
                                    Time after operation (years)                                                             Time after operation (years)


 Figure 6 Survival (left) and event-free survival (right) after aortic valve replacement with Starr-Edwards valve (Carpentier-Edwards,
 Irvine, Calif) and St Jude valve (St Jude Medical Inc, St Paul, Minn). Data with mitral valve replacement were similar. Adapted with
 permission from Murday AJ, Hochstizky A, Mansfield J, et al. A prospective controlled trial of St. Jude versus Starr Edwards aortic and
 mitral valve prostheses. Ann Thorac Surg. 203;76:66-74.



SURGERY                                                                                    resumed an active life; 1 patient is known to have survived
                                                                                           another 31 years. This epochal event was followed in 1963
Open Heart Surgery                                                                         and 1964 by an astounding surgical accomplishment dem-
In 1954, John Gibbon Jr52 described the use of total cardio-                               onstrating that valve replacement could be “safe.” McGoon
pulmonary bypass for intracardiac surgery. This had an                                     et al55 replaced native aortic valves with Starr-Edwards
enormous impact on valve surgery and completely changed                                    valves (Edwards Life Sciences, Irvine, Calif) in 100 con-
its performance. Valve surgery has been the most important                                 secutive patients, most of whom were in severe heart fail-
advance in the treatment of symptomatic patients with se-                                  ure, and all of the patients survived. Since 1960, Starr and
vere valve disease. Valve surgery markedly improves func-                                  colleagues have used the Starr-Edwards valve in 3653 pa-
tional class, hemodynamics, and left ventricular function. It                              tients, 1 of whom survived 41 years.56 After improvements
also has improved survival in patients with severe aortic or                               to the original model in 1965, the Starr-Edwards valve has
mitral valve stenosis (Figures 2 and 4), and probably has                                  remained virtually unchanged, and no structural valve de-
improved survival in symptomatic patients with severe aor-                                 terioration has yet been observed. A randomized trial has
tic or mitral regurgitation.                                                               shown that Starr-Edwards and newer St Jude (St Jude Med-
                                                                                           ical Inc, St Paul, Minn) valves yield equally favorable
                                                                                           outcomes up to 8 years of follow-up (Figure 6).57
Valve Replacement                                                                              Xenografts (heterografts) were first used in 1965 by
Prosthetic heart valves are mechanical or biological. Bio-                                 Carpentier et al,58 who coined the term “bioprosthesis.”59
logical valves can be derived from patient tissues (au-                                    Ross60 used autografts in 1967.
tografts) or donor tissues (allografts, called homografts), or                                 Procedures involving stentless bioprostheses, homografts,
can be valves taken from another species (xenografts, called                               or the “Ross principle” require aortic root replacement with
“bioprosthesis”).                                                                          reimplantation of coronary arteries, which poses a problem
   Mechanical prosthetic heart valves were used in 1960 by                                 if reoperation is needed. Furthermore, data from more
Harken and Starr. It was the initial results obtained by Starr                             than 400,000 patients from the Society of Thoracic Sur-
and Edwards53,54 that changed the scene. Of Starr and                                      gery database have shown that the operative mortality for
Edwards’ first 8 patients, all of whom were in advanced                                     these procedures is approximately twice that for stented
heart failure, 6 survived to leave the hospital and several                                bioprosthesis.61
Sharma et al                                     Valve Disease                                                                                            671

   The 2 largest randomized trials, the Edinburgh Heart
Valve trial62 and the Veterans Administration trial,63 com-
pared a mechanical valve (original Delron-ring Bjork-
Shiley valve [Shiley Labs, Irvine, Calif]) with a porcine
bioprosthesis (Figures 7 and 8). The findings were similar:
There was no significant difference in survival over 20
years with 1 exception (discussed below); there were no
significant differences in thromboembolism, infective en-
docarditis, or all-cause complications; the mechanical
valves did not deteriorate, but they had a higher rate of
bleeding; and the bioprosthetic valves deteriorated at an
increasing rate. Only the Veterans Administration trial, in
which a larger number of patients underwent aortic valve
replacement, showed a higher mortality for the porcine
valve because of structural deterioration; however, no                                        Figure 8 Department of Veterans Affairs trial of valvular
deterioration was observed in patients who were at least                                      heart disease. Fifteen-year survival after aortic valve replace-
65 years old at the time of valve replacement.                                                ment is better with a mechanical valve than with a bioprosthetic
   The current choice is usually a mechanical valve or                                        porcine valve because of structural valve deterioration of the
stented bioprosthesis.64 The choice between the 2 types of                                    porcine bioprosthetic valve. With permission from Hammer-
                                                                                              meister KE, Sethi GK, Henderson WG, et al. Outcomes 15 years
prosthetic heart valves is a choice between which compli-
                                                                                              after valve replacement with a mechanical versus a bioprosthetic
cation is a greater problem for an individual patient and to                                  valve: final report of the VA randomized trial. J Am Coll Car-
be avoided: anticoagulants and its complications with a                                       diol. 2000;36:1152-1158. DVA developmental venous anom-
mechanical valve or the structural valve deterioration and its                                aly; VHD         valvular heart disease; AVR        aortic valve
complications with the use of a bioprosthesis. Patients un-                                   replacement.
dergoing aortic valve replacement who are at least 60 to 65
years of age should receive a bioprosthesis. Current data
indicate that the Carpentier-Edwards pericardial valve has a
                                                                                              vival after valve replacement depends largely on patient-
lower rate of structural deterioration than a porcine pros-
                                                                                              related factors.63,65
thetic heart valve.64 In the Veterans Administration trial,
                                                                                                 All prosthetic heart valves are smaller in area than the
only 40% to 50% of the deaths after valve replacement
                                                                                              native human valve and thus have the problem of valve
were related to the prosthetic valve, confirming that sur-
                                                                                              prosthesis–patient mismatch.40 After aortic valve replace-
                                                                                              ment, severe mismatch (valve area 0.6 cm2/m2) is asso-
                                   100                                                        ciated with significant morbidity and increased mortality.64

                                                                                              Valve Repair
  original prosthesis intact (%)




                                    80
                                                              AVR                             Aortic Valve. Aortic valve repair is performed most often
     Patients surviving with




                                                                                              for congenital aortic stenosis with mobile, noncalcified aor-
                                    60
                                                                                              tic valves. Many of these valves are suitable for catheter
                                                                                              balloon commissurotomy. Repair also is performed in se-
                                                  MVR                                         lected patients with severe aortic regurgitation.
                                    40
                                                                                              Mitral Valve. After Lillehei performed mitral valve repair
                                                                                              to treat mitral regurgitation in 1957,65 many more surgeons,
                                    20            Mechanical                                  including McGoon and Kay, advocated and practiced the
                                                  Bioporosthesis
                                                                                              procedure. It became even more popular in the 1970s, with
                                                                                              the elegant repair methods of Carpentier and Duran,65 and
                                     0
                                         0   2     4    6   8 10 12 14 16           18   20   again after 1983, when Carpentier66 described his sophisti-
                                                        Years after randomization             cated “French correction.” A major advantage to mitral
                                                                                              valve repair, as opposed to replacement, is that it circum-
Figure 7 Survival with original valve after aortic valve re-                                  vents both the complications of prosthetic valves and the
placement and mitral valve replacement in the Edinburgh Heart                                 need for anticoagulation therapy associated with mechanical
Valve trial. Adapted from Oxenham H, Bloomfield P, Wheatley                                    prosthetics.
DJ, et al. Twenty year comparison of a Bjork-Shiley mechanical
heart valve with porcine bioprostheses. Heart. 2003;89:715-721.
AVR         aortic valve replacement; MVR          mitral valve
                                                                                              Valve Surgery and Coronary Artery Disease. A combi-
replacement.                                                                                  nation of valve surgery and coronary artery bypass graft
                                                                                              surgery is the routine procedure in these patients.
672                                                                         The American Journal of Medicine, Vol 121, No 8, August 2008

                                                                                14. Lagerlöf H, Werkö L. Studies on the circulation of blood in man VI.
Table 5 Some Desirable Progress in the Future of Valvular                           The pulmonary capillary venous pressure pulse in man. Scand J Clin
Heart Disease                                                                       Lab Invest. 1949;1:147-161.
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                                                                                    recording of the movements of heart walls. Kunglia Fysiografska
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Valvular Heart Disease A Century Of Progress

  • 1. REVIEW Valvular Heart Disease: A Century of Progress Sanjay Sharma, MD, Anilkumar Mehra, MD, Shahbudin H. Rahimtoola, MB, FRCP, DSc (Hon) 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, Calif. ABSTRACT The 20th century witnessed amazing advances in the diagnosis and treatment of valvular heart disease. The advances and our hopes for future progress are described. © 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, 664-673 KEYWORDS: Cardiac catheterization; Doppler echocardiography; Percutaneous catheter intervention; Valve surgery “How can you understand the world if you don’t know what the Medical Research Council, he advocated prospective happened in it?” follow-up studies, or “after-histories,” of patients. These —John W. Kirklin, MD1 after-histories5 were the predecessors of databases and reg- Since the turn of the 20th century, extraordinary ad- istries in use today. vances have been made in the diagnosis and treatment of According to Feinstein,6 the first randomized controlled valvular heart disease. Some of the major achievements study in scientific literature was reported in agricultural underlying these advances have received due recognition experiments carried out by T. Eden in 1923 on the effect of (Table 1).2 Breakthroughs in medicine are a culmination of manure on potato crops. The first randomized clinical trial small advances3 in valvular heart disease. Different small in valvular heart disease began in 1954.7 The 5-year results advances occurred in both halves of the century (Tables are shown in Table 4.8 2 and 3). Rheumatic Fever and Carditis THE FIRST HALF OF THE LAST CENTURY In the first half of the 20th century, rheumatic heart disease was a major problem; for example, in Britain, rheumatic Setting the Stage heart disease accounted for 20% of all heart disease and During World War I, Lewis,4 charged with the care of 10,000 deaths annually.9 combatants with heart disease, noted the inadequate under- The observations that led to the conquering of this standing of cardiac disease and its prognosis. In a report to scourge merit a brief review.10 From an epidemiologic sur- vey, Newsholme11 correctly deduced that an active infective Dr Rahimtoola has received honoraria for educational lectures from the agent and conditions of environmental and personal factors American College of Cardiology Foundation (Washington, DC); American were required for the development of rheumatic fever. College of Physicians (Philadelphia, Pa); University of California Los Aschoff described the specific rheumatic lesion (Aschoff Angeles; University of California Irvine; Cornell University (New York, NY); Creighton University (Omaha, Neb); Thomas Jefferson University body).10 In the late 1920s, Griffith and Lancefield identified (Philadelphia, Pa); Cedars-Sinai Medical Center (Los Angeles, Calif); Group A hemolytic streptococcus as the causative organ- Harvard Medical School (Boston, Mass); University of Wisconsin (Mil- ism.10 Centers were established in New York, Boston, and waukee Campus, Wis); University of Hawaii (Honolulu, Hawaii); Cardi- London for the long-term care of these patients. In 1944, ologists Association of Hong Kong, China; ATS (New York, NY); St Jude Medical (St Paul, Minn); Carbomedics (Austin, Tex); Merck (Whitehouse Jones12 published his seminal work on the diagnosis of rheu- Station, NJ); Pfizer (New York, NY); and Edwards Life Sciences (Irvine, matic fever. In Denmark, improvements in socioeconomic Calif). conditions and housing dramatically reduced the incidence Requests for reprints should be addressed to Shahbudin H. Rahimtoola, of rheumatic fever before the antibiotic era (Figure 1).10 MD, University of Southern California, 2025 Zonal Avenue, GNH 7131, Los Angeles, CA 90033. Rheumatic carditis and valve disease have been virtually E-mail address: rahimtoo@usc.edu eliminated from developed countries, similar to the virtual 0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.03.027
  • 2. Sharma et al Valve Disease 665 elimination of smallpox and poliomyelitis in the world by Coronary Arteriography. Sones and colleagues22 obtained vaccines. a selective coronary arteriogram by inadvertently engaging the right coronary artery during an aortogram. Subse- quently, coronary arteriography became routine in clinical THE SECOND HALF OF THE TWENTIETH CENTURY practice but required arterial cutdown. The development of Patient Assessment a percutaneous arterial access Pressure Measurement. Efforts technique by Seldinger16 and of to quantify the severity of valvular preformed catheters by Judkins23 CLINICAL SIGNIFICANCE heart disease began in 1945 with made coronary arteriography fea- attempts to measure intracardiac ● The diagnosis and assessment of the se- sible for widespread use. The data pressures. In landmark studies, verity of valve stenosis and regurgitation obtained by catheterization, ven- 13 Hellems et al and Lagerlöf and are at an advanced level of accuracy. tricular and aortic angiography, 14 Werkö documented that pres- and selective coronary arteriogra- ● Interventional therapy in patients with phy are the foundation for evalu- sures recorded with a cardiac cathe- ter wedged into the distal pulmonary valvular heart disease results in an im- ation of valvular heart disease. artery reflected left atrial pressure. provement of symptoms, functional class, Ross15 developed the transseptal left ventricular function, and pulmonary Doppler Echocardiography and approach to the left ventricle. Per- hypertension. Survival is improved in Ultrasonography. Edler and cutaneous transthoracic puncture many patients. Hertz,24 using ultrasonography, of the left ventricle was used to first recorded the movement of ● All patients should be considered poten- cardiac structures in 1953. Early measure left ventricular pressure in aortic stenosis. Subsequently, the tial candidates for interventional therapy M-mode echocardiography was Seldinger16 technique for percuta- and should undergo appropriate clinical effective in the diagnosis of mitral neous entry into a systemic artery evaluation and diagnostic testing. stenosis; 2-dimensional echocar- revolutionized retrograde access diography allowed for real-time to the ascending aorta and left visual morphologic evaluation of ventricle. cardiac structure and function. Su- perimposition of Doppler by Hatle and colleagues25 allowed Valve Area Calculations. By comparing hydraulic systems for indirect hemodynamic measurement. Transesophageal and cardiac physiology, Gorlin and Gorlin17 derived the echocardiography increased the clarity and accuracy of a following formula for calculating mitral and aortic valve number of valvular heart diseases. areas: Echocardiography/Doppler permitted the rapid initial as- sessment of patients with mild, moderate, or severe valvular CO/HR DFP mitral valve area heart disease. It also was of great value not only in diag- 37'.9' gradient nosing unsuspected lesions but also in excluding disease. Along with the chest x-ray and the electrocardiogram, echo- CO/HR SEP' cardiography/Doppler has become an essential component aortic valve area 44'.3' gradient' of the clinical evaluation of patients with valvular heart disease. Computed tomography, electron beam computed where CO cardiac output, HR heart rate, DFP tomography, and cardiac magnetic resonance imaging have diastolic filling period, and SEP systolic ejection period. not been proven superior to echocardiography/Doppler for this purpose. Angiography. The first angiocardiogram in humans was 18 performed by Castellanos and colleagues. Aortography and left ventricular angiography were essential to assessing INDIVIDUAL LESIONS aortic and mitral regurgitation. Dodge and colleagues19 ac- curately calculated the left ventricular volumes and ejection Mitral Stenosis fraction from left ventricular angiograms using Arvidsson’s In 1954, the outstanding clinical cardiologist and scholar technique. Paul Wood26 described the clinical features, pathophysiol- ogy, complications, and outcomes of mitral stenosis. He Normal Values. Values for right-sided heart pressures, pul- documented that, on average, the symptoms of mitral ste- monary artery wedge pressure, and cardiac output were nosis began 19 years after rheumatic carditis. documented in healthy volunteers.20 Another study in As early as the 1920s, but mainly in the early 1950s, healthy subjects documented right and left-sided heart pres- mitral commissurotomy was performed by manual dilata- sures and left ventricular volumes and ejection fraction.21 tion (“finger fracture”).27 Later in the 1950s, the results The normal cardiac index was found to be 3.6 0.9 were improved by using the Tubbs’ dilator, which is intro- L/min/m2. duced from the left ventricular apex. Both of these proce-
  • 3. 666 The American Journal of Medicine, Vol 121, No 8, August 2008 dures were “blind” (closed). When performed by a skilled, Table 2 Procedural Advances in Valvular Heart Disease experienced surgeon on an appropriate patient, closed mitral commissurotomy had an excellent outcome; the survival Discoveries by 6 Nobel Laureates who have had an impact on was better than that of medical therapy (Figure 2),28 and the valvular heart disease 24-year survival was 84%.27 The next development was Identification of the infecting organism of rheumatic fever “open” mitral commissurotomy, which incorporated extra- Establishment of databases Performance of randomized clinical trials corporeal circulation. However, in skilled surgical hands, Measurement of intracardiac pressures and calculation of valve the results of closed and open mitral commissurotomies areas were similar.29 In the early 1960s, mitral valve replacement Left ventricular angiography, aortography, coronary provided excellent results for those patients who were poor arteriography candidates for surgical commissurotomy.30 Echocardiography/Doppler The 1980s ushered in the era of catheter balloon com- Total cardiopulmonary bypass for intracardiac surgery missurotomy; the double balloon technique was followed by Cardiac Surgery: the Inoue balloon (Toray Medical Co, Ltd), which is still in Commissurotomy current use. In randomized trials, catheter balloon commis- Prosthetic heart valves surotomy yielded outcomes at least as good as those ob- Valve repair tained from closed or open surgical commissurotomy.31 Robotic surgery Coronary artery bypass graft surgery All 3 procedures yield the best results for mobile and Percutaneous catheter intervention for coronary artery disease Catheter balloon commissurotomy Table 1 Nobel Prize and Lasker Award-winning Achievements Relevant to Valvular Heart Disease Wilhelm Conrad Röntgen The Nobel Prize in Physics 1901 “In recognition of the extraordinary services he has rendered by the discovery of the remarkable rays Table 3 Accomplishments in Valvular Heart Disease subsequently named after him” Alexis Carrel The Nobel Prize in Physiology or Virtual elimination of rheumatic valve disease in developed Medicine 1912 countries “In recognition of his work on Reduction of rheumatic fever, rheumatic fever recurrences, and vascular suture and the rheumatic valve disease in developing countries transplantation of blood vessels Recognition of drug-induced valve disease and organs” More accurate diagnosis of valve disease and assessment of Willem Einthoven The Nobel Prize in Physiology or their severity Medicine 1924 Significantly better assessment of severity of valve diseases “For his discovery of the mechanism Definition of valvular abnormality/pathology of the electrocardiogram” Correction of valve abnormality/pathology Gerhard Domagk The Nobel Prize in Physiology or Relief of mitral stenosis by percutaneous catheter technique Medicine 1939 Appropriate selection of valve replacement device and procedure “for the discovery of the antibacterial resulting in improvement of symptoms, functional status, effects of prontosil”* left ventricular function, pulmonary hypertension, and Sir Alexander Fleming, The Nobel Prize in Physiology or survival Ernst Boris Chain, Sir Medicine 1945 Howard Walter Florey “for the discovery of penicillin and its curative effect in various infectious diseases” André Frédéric The Nobel Prize in Physiology or Cournand, Werner Medicine 1956 Table 4 Recurrence of Rheumatic Fever* Forssmann, Dickinson W. “for their discoveries concerning Richards heart catheterization and Per Compliance pathological changes in the Year, % Rate, % circulatory system” Benzathine penicillin, 1.2 million 0.4 94 Albert Starr, Alain Albert Lasker Clinical Research Award (intramuscular) every 4 wk Carpentier 2007 Oral penicillin G, 200,000 U once daily 5.5 50 “Surgeon-scientists who Sulfadiazine, 1 g/d 2.8 50 revolutionized the treatment of *Data from Alban B, Epstein JA, Feinstein AR. Rheumatic fever in heart disease” children and adolescents: a long-term epidemiologic study of subsequent *Protonsil was the first synthetic drug used for treatment of general prophylaxis, streptococcal infection and clinical sequelae. Ann Intern bacterial infections in humans. Med. 1964;60(Suppl 5):1-129.
  • 4. Sharma et al Valve Disease 667 matic fever and carditis: On average, symptoms of aortic re- Reported Rheumatic Fever, Denmark, 1862-1962 gurgitation began 20 years after the occurrence of carditis. 300 The incidence of death, angina, or heart failure was 87% at 200 6 years in the high-risk group and 8% at 15 years in the low-risk group.32 In the current era, aortic regurgitation is MORBIDITY PER 100,000 Penicillin usually the result of aortic root dilation with echocardiog- 100 raphy/Doppler used to study the natural history.31 Of asymptomatic patients with normal left ventricular ejection 50 fraction, approximately 3% to 6% per year become symptom- atic or progress to left ventricular dysfunction; more than one quarter of patients with left ventricular dysfunction become 20 symptomatic per year; and the mortality for symptomatic patients is more than 10% per year. In addition, echocar- 10 1860 ‘70 ‘80 ‘90 1900 ‘10 ‘20 ‘30 ‘40 ‘50 ‘60 ‘70 diographic data for left ventricular dimensions show that an YEAR end-diastolic dimension of 70 mm ( 35 mm/m2) or an end-systolic dimension of 50 mm ( 25 mm/m2) increases Figure 1 Incidence of rheumatic fever in Denmark from 1862 to 1962. From the Public Health Board of Denmark, Copenha- the chance that a patient will become symptomatic or de- gen, Denmark. This is a log scale; from 1860 to 1945 morbidity velop left ventricular dysfunction.31 Left ventricular dys- decreased by approximately 75%. The time when penicillin was function precedes the development of symptoms in more available for clinical use (arrow). Adapted from Stollerman GH. than half of asymptomatic patients.31,33 Rheumatic Fever and Streptococcal Infections. New York: Arteriolar dilators were shown to have beneficial effects Grune & Stratton, Inc. 1975;21-146. on hemodynamics and left ventricular size during 1 year of follow-up. These data set the stage for a randomized trial documenting that long-acting nifedipine reduced or de- nonthickened or mildly thickened valves. Catheter bal- layed the need for aortic valve replacement in asymp- loon commissurotomy is now the first-line treatment for tomatic patients with normal left ventricular ejection mitral stenosis.30 fraction (Figure 3).33 In all symptomatic patients, aortic valve replacement was shown to have beneficial effects on Aortic Regurgitation symptoms, as well as left ventricular size and function, even Most patients described in the after-histories of Lewis4 had when baseline left ventricular systolic function was abnor- chronic aortic regurgitation. There were 3 eras.32 The era of mal;34 minimally symptomatic and asymptomatic patients syphilis: The data are largely from the preantibiotic era; with mild left ventricular dysfunction have the best out- syphilitic cardiovascular disease is now rare. The era of rheu- comes from the procedure.35 MITRAL STENOSIS MITRAL STENOSIS (Functional Class II) (Functional Class III & IV) Figure 2 Closed mitral commissurotomy is associated with better survival than medical therapy in patients with severe mitral stenosis who were mildly symptomatic (left) and severely symptomatic (right). Adapted from Roy SB, Gopinath N. Mitral stenosis. Circu- lation. 1968;38(suppl V):68-76.
  • 5. 668 The American Journal of Medicine, Vol 121, No 8, August 2008 occur in older patients. Atherosclerosis and inflammation are important factors in the complex cause of calcific aortic stenosis.36,37 The life expectancy of patients has markedly increased; calcific aortic stenosis is now the most common reason for valve replacement. In 1968, an analysis of autopsy data showed a 3-year average life expectancy for symptomatic patients with se- vere aortic stenosis.38 Twenty years later, a follow-up study after cardiac catheterization confirmed the short life expect- ancy.39 In both studies, life expectancy after the onset of heart failure was only 1 to 2 years. In the 1970s, the importance of correcting aortic valve areas for body size was recognized.40 Severe aortic stenosis was diagnosed as aortic valve areas of 1.0 cm2 or less ( 0.6 cm2/m2);41 more recently, severe aortic stenosis was defined as an aortic valve area of 0.7 cm2 or less ( 0.4 cm2/m2). A Figure 3 Long-acting nifedipine administered twice daily re- mean aortic valve gradient of 50 mm Hg or more is usually sults in a lower incidence of the need for aortic valve replace- a reliable indicator of severe aortic stenosis.42 ment in asymptomatic patients with chronic severe aortic regur- gitation and normal left ventricular ejection fraction. From In symptomatic patients with severe aortic stenosis, aor- Scognamiglio R, Rahimtoola SH, Fasoli G, et al. Nifedipine in tic valve replacement has a beneficial effect on symptoms, asymptomatic patients with severe aortic regurgitation and nor- left ventricular function, left ventricular hypertrophy, and mal left ventricular function. N Engl J Med. 1994;331:689-695. survival (Figure 4).39,43 It also markedly improves symp- PTS patients; AR aortic regurgitation; LV left ventricular. toms in patients with severe aortic stenosis and clinical heart failure; if patients have no history of myocardial infarction and the procedure is performed early, the left ventricular Aortic Stenosis ejection fraction normalizes in one half to two thirds of Most cases of severe aortic stenosis currently seen in de- patients (Figure 5).44 These positive outcomes also occur in veloped countries are calcific (so-called degenerative) and patients with aortic stenosis, low aortic valve gradients, and operated operated non-operated non-operated non- A B Figure 4 Survival is better after aortic valve replacement (operated) than with medical therapy (non-operated) in patients with severe aortic stenosis. A: Adapted from Schwarz F, Banmann P, Manthey J, et al. The effect of aortic valve replacement on survival. Circu- lation. 1982;66:1105-1110. B: Adapted from Horstkotte D, Loogen F. The natural history of aortic valve stenosis. Eur Heart J. 1988;9(suppl E):57-64.
  • 6. Sharma et al Valve Disease 669 a complication of the dilated orifice and diseased valve. The subsequent results depend on the degree of the exhaustion AVR FOR AS IN HEART FAILURE of the muscle of the heart. The backward pressure resulting 1.0 from the regurgitation embarrasses the left auricle, pulmo- nary circulation, and right heart.” These observations, made in 1908, are valid even now. 0.9 mean ± SE The incidence of mitral regurgitation in patients with rheumatic valve disease was documented to be 34%.9 In 0.8 the late 1950s, ruptured chordae tendineae were recog- nized as the cause of acute mitral regurgitation. At the EJECTION FRACTION 0.7 1958 Goulstonian Lecture, Leatham47 gave his classic presentation on auscultation of the heart. However, he thought that late systolic sounds were pericardial/pleural 0.6 in origin and that the accompanying murmur was “innocent” (Figure 16 in his article).47 Also in 1958, 0.5 McKusick48 wrote a treatise on cardiovascular sounds, describing in considerable detail a “musical pleural peri- 0.4 cardial murmur” often preceded by a click. He noted that this sound had been described earlier, first in 1843 in 0.3 patients with valves later determined at autopsy to be “normal,” and then in 1880 by Osler.48 In 1963, on the basis of autopsy findings, Barlow and 0.2 colleagues49 described mitral valve prolapse as a cause of these sounds. Subsequently, mitral valve prolapse was 0.1 P<0.001 diagnosed clinically by left ventricular angiography. Echocardiography/Doppler represented a major advance 0 that not only provided evidence of the causes of mitral Pre-Op Post-Op regurgitation, including mitral valve prolapse, and the Peri-Op MI and late CHB pathophysiologic changes associated with mitral regurgi- Post-Op: Perivalvular Aortic Regurgitation tation, but also showed that mitral valve prolapse is common and the most common cause of ruptured chordae Figure 5 Left ventricular ejection fraction improves and even tendineae, which became known as “flail leaflets.” Mitral normalizes after aortic valve replacement in approximately two regurgitation also can be caused by coronary artery dis- thirds of patients with severe aortic stenosis and clinical heart ease because of its effect on the left ventricle. Recently, failure. Adapted from Smith N, McAnulty JH, Rahimtoola SH. some drugs also have been shown to cause valvular Severe aortic stenosis with impaired left ventricular function regurgitation.50 and clinical heart failure. Results of valve replacement. Circu- Symptomatic patients with severe mitral regurgitation lation. 1978;58:255-264. AVR aortic valve replacement; SE benefited from mitral valve replacement or repair. In asymp- standard error; MI myocardial infarction; CHB com- plete heart block. tomatic patients, mitral valve replacement or repair can be deferred until the onset of symptoms or evidence of left ventricular dysfunction, pulmonary hypertension, or atrial fibrillation.51 severe left ventricular dysfunction if they have severe aortic stenosis.45 Tricuspid Valve Disease In 1908 Mackenzie46 observed, “Although actual disease Mitral Regurgitation of the valves is rare, incompetence of the tricuspid orifice In the early 1900s, mitral regurgitation was the most is extremely common . . . It should never be concluded commonly diagnosed valve lesion. At that time, physi- that no tricuspid regurgitation occurs because of the ab- cians were strongly discouraged from overdiagnosing sence of a murmur . . . A weak muscular wall and wide organic mitral regurgitation, thus saving healthy subjects orifice may give rise to no murmur.” These observations from invalidism.9 remain relevant even today, and good methods for repair- Mackenzie46 was well aware of the spectrum of the ing or replacing tricuspid valves are still lacking. There is clinical aspects of mitral regurgitation, writing, “The really a great need for improvements in surgical techniques, serious trouble in connexion with mitral regurgitation arises replacement valves, and assessment of patients for when the muscle is impaired and the regurgitation is due to surgery.
  • 7. 670 The American Journal of Medicine, Vol 121, No 8, August 2008 Starr-Edwards Starr- St. Jude 100 100 90 90 80 80 vent-free urvival (%) 70 70 Survival (%) 60 60 50 50 40 40 S n=122 n=113 n=104 n=93 n=75 n=59 n=38 n=21 n=112 n=101 n=85 n=75 n=55 n=42 n=25 n=12 30 30 20 20 E n=118 n=110 n=102 n=90 n=78 n=60 n=44 n=24 n=106 n=92 n=83 n=72 n=59 n=45 n=32 n=17 10 10 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Time after operation (years) Time after operation (years) Figure 6 Survival (left) and event-free survival (right) after aortic valve replacement with Starr-Edwards valve (Carpentier-Edwards, Irvine, Calif) and St Jude valve (St Jude Medical Inc, St Paul, Minn). Data with mitral valve replacement were similar. Adapted with permission from Murday AJ, Hochstizky A, Mansfield J, et al. A prospective controlled trial of St. Jude versus Starr Edwards aortic and mitral valve prostheses. Ann Thorac Surg. 203;76:66-74. SURGERY resumed an active life; 1 patient is known to have survived another 31 years. This epochal event was followed in 1963 Open Heart Surgery and 1964 by an astounding surgical accomplishment dem- In 1954, John Gibbon Jr52 described the use of total cardio- onstrating that valve replacement could be “safe.” McGoon pulmonary bypass for intracardiac surgery. This had an et al55 replaced native aortic valves with Starr-Edwards enormous impact on valve surgery and completely changed valves (Edwards Life Sciences, Irvine, Calif) in 100 con- its performance. Valve surgery has been the most important secutive patients, most of whom were in severe heart fail- advance in the treatment of symptomatic patients with se- ure, and all of the patients survived. Since 1960, Starr and vere valve disease. Valve surgery markedly improves func- colleagues have used the Starr-Edwards valve in 3653 pa- tional class, hemodynamics, and left ventricular function. It tients, 1 of whom survived 41 years.56 After improvements also has improved survival in patients with severe aortic or to the original model in 1965, the Starr-Edwards valve has mitral valve stenosis (Figures 2 and 4), and probably has remained virtually unchanged, and no structural valve de- improved survival in symptomatic patients with severe aor- terioration has yet been observed. A randomized trial has tic or mitral regurgitation. shown that Starr-Edwards and newer St Jude (St Jude Med- ical Inc, St Paul, Minn) valves yield equally favorable outcomes up to 8 years of follow-up (Figure 6).57 Valve Replacement Xenografts (heterografts) were first used in 1965 by Prosthetic heart valves are mechanical or biological. Bio- Carpentier et al,58 who coined the term “bioprosthesis.”59 logical valves can be derived from patient tissues (au- Ross60 used autografts in 1967. tografts) or donor tissues (allografts, called homografts), or Procedures involving stentless bioprostheses, homografts, can be valves taken from another species (xenografts, called or the “Ross principle” require aortic root replacement with “bioprosthesis”). reimplantation of coronary arteries, which poses a problem Mechanical prosthetic heart valves were used in 1960 by if reoperation is needed. Furthermore, data from more Harken and Starr. It was the initial results obtained by Starr than 400,000 patients from the Society of Thoracic Sur- and Edwards53,54 that changed the scene. Of Starr and gery database have shown that the operative mortality for Edwards’ first 8 patients, all of whom were in advanced these procedures is approximately twice that for stented heart failure, 6 survived to leave the hospital and several bioprosthesis.61
  • 8. Sharma et al Valve Disease 671 The 2 largest randomized trials, the Edinburgh Heart Valve trial62 and the Veterans Administration trial,63 com- pared a mechanical valve (original Delron-ring Bjork- Shiley valve [Shiley Labs, Irvine, Calif]) with a porcine bioprosthesis (Figures 7 and 8). The findings were similar: There was no significant difference in survival over 20 years with 1 exception (discussed below); there were no significant differences in thromboembolism, infective en- docarditis, or all-cause complications; the mechanical valves did not deteriorate, but they had a higher rate of bleeding; and the bioprosthetic valves deteriorated at an increasing rate. Only the Veterans Administration trial, in which a larger number of patients underwent aortic valve replacement, showed a higher mortality for the porcine valve because of structural deterioration; however, no Figure 8 Department of Veterans Affairs trial of valvular deterioration was observed in patients who were at least heart disease. Fifteen-year survival after aortic valve replace- 65 years old at the time of valve replacement. ment is better with a mechanical valve than with a bioprosthetic The current choice is usually a mechanical valve or porcine valve because of structural valve deterioration of the stented bioprosthesis.64 The choice between the 2 types of porcine bioprosthetic valve. With permission from Hammer- meister KE, Sethi GK, Henderson WG, et al. Outcomes 15 years prosthetic heart valves is a choice between which compli- after valve replacement with a mechanical versus a bioprosthetic cation is a greater problem for an individual patient and to valve: final report of the VA randomized trial. J Am Coll Car- be avoided: anticoagulants and its complications with a diol. 2000;36:1152-1158. DVA developmental venous anom- mechanical valve or the structural valve deterioration and its aly; VHD valvular heart disease; AVR aortic valve complications with the use of a bioprosthesis. Patients un- replacement. dergoing aortic valve replacement who are at least 60 to 65 years of age should receive a bioprosthesis. Current data indicate that the Carpentier-Edwards pericardial valve has a vival after valve replacement depends largely on patient- lower rate of structural deterioration than a porcine pros- related factors.63,65 thetic heart valve.64 In the Veterans Administration trial, All prosthetic heart valves are smaller in area than the only 40% to 50% of the deaths after valve replacement native human valve and thus have the problem of valve were related to the prosthetic valve, confirming that sur- prosthesis–patient mismatch.40 After aortic valve replace- ment, severe mismatch (valve area 0.6 cm2/m2) is asso- 100 ciated with significant morbidity and increased mortality.64 Valve Repair original prosthesis intact (%) 80 AVR Aortic Valve. Aortic valve repair is performed most often Patients surviving with for congenital aortic stenosis with mobile, noncalcified aor- 60 tic valves. Many of these valves are suitable for catheter balloon commissurotomy. Repair also is performed in se- MVR lected patients with severe aortic regurgitation. 40 Mitral Valve. After Lillehei performed mitral valve repair to treat mitral regurgitation in 1957,65 many more surgeons, 20 Mechanical including McGoon and Kay, advocated and practiced the Bioporosthesis procedure. It became even more popular in the 1970s, with the elegant repair methods of Carpentier and Duran,65 and 0 0 2 4 6 8 10 12 14 16 18 20 again after 1983, when Carpentier66 described his sophisti- Years after randomization cated “French correction.” A major advantage to mitral valve repair, as opposed to replacement, is that it circum- Figure 7 Survival with original valve after aortic valve re- vents both the complications of prosthetic valves and the placement and mitral valve replacement in the Edinburgh Heart need for anticoagulation therapy associated with mechanical Valve trial. Adapted from Oxenham H, Bloomfield P, Wheatley prosthetics. DJ, et al. Twenty year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses. Heart. 2003;89:715-721. AVR aortic valve replacement; MVR mitral valve Valve Surgery and Coronary Artery Disease. A combi- replacement. nation of valve surgery and coronary artery bypass graft surgery is the routine procedure in these patients.
  • 9. 672 The American Journal of Medicine, Vol 121, No 8, August 2008 14. Lagerlöf H, Werkö L. Studies on the circulation of blood in man VI. Table 5 Some Desirable Progress in the Future of Valvular The pulmonary capillary venous pressure pulse in man. Scand J Clin Heart Disease Lab Invest. 1949;1:147-161. 15. Ross J, Jr. Transseptal left heart catheterization: a new method of left Elimination, or at least marked reduction, of rheumatic heart arterial puncture. Ann Surg. 1959;149:395-401. disease in developing countries 16. Seldinger SI. Catheter replacement of the needle in percutaneous Better knowledge of the development and growth of native arteriography; a new technique. Acta Radiol. 1953;39:368-376. valves, including the role of genetics and other factors 17. Gorlin R, Gorlin SG. Hydraulic formula for the calculation of the More accurate and complete knowledge of the causes of valve stenotic mitral valve, other cardiac valves, and central circulatory disease shunts. Am Heart J. 1951;41:1-29. Better assessment of severity of valve stenosis 18. Castellanos A, Pereiras R, Garcia AA. L’angio-cardiogra radio-opaca More accurate measured quantitative assessment of valve chez l’enfant. Arch Estud Clin Habana. 1937;31:523-527. regurgitation 19. Dodge HT, Sandler H, Ballew DW, et al. The use of biplane angio- More precise and accurate documentation of the natural history cardiography for the measurement of left ventricular volume in man. Am Heart J. 1960;60:762-776. of all asymptomatic patients with severe, moderate, and mild 20. Barrat-Boyes B, Wood EH. Cardiac output and related measurement valve disease and pressure values in the right heart and associated vessels, response Better therapeutic options: to the inhalation of high oxygen mixtures in healthy subjects. J Lab Pharmacologic agents for primary and secondary prevention Clin Med. 1958;51:72-90. Optimal timing of invasive procedures 21. Ehsani, Rahimtoola SH, Sinno MZ, et al. Left ventricular performance Better PHV, including tissue-engineered (including stem cell) during convalescent phase of myocardial infection. Arch Int Med. PHV 1975;135:1539-1575. Percutaneous therapeutic procedures 22. Sones FM, Jr, Shirey EK, Prondfit WL, et al. Cinecoronary arteriog- Better therapeutic options for tricuspid valve disease raphy. Circulation. 1959;20:773. Hybrid procedures (valve replacement CABG/PCI), performed 23. Judkins MP. Selective coronary arteriography: a percutaneous trans- femoral technique. Radiology. 1967;89:815-824. in a combined catheterization laboratory operating room 24. Edler I, Hertz CH. Use of ultrasonic reflectoscope for the continuous Early diagnosis and treatment of emergencies in valvular heart recording of the movements of heart walls. Kunglia Fysiografska disease Sallskapets I Lund Frohandlingar. 1954;24:1-19. PHV prosthetic heart valve; CABG coronary bypass graft surgery; 25. Hatle L, Angelsen BA, Tromsdal A. Non-invasive assessment of aortic PCI percutaneous catheter intervention. stenosis by Doppler ultrasound. Br Heart J. 1980;43:284-292. 26. Wood P. An appreciation of mitral stenosis. Br Med J. 1954;1:1051- 1063, 1113-1124. 27. John S, Bashi VV, Jairaj PS, et al. Closed mitral valvotomy: early FUTURE DIRECTIONS results and long term follow-up of 3724 consecutive patients. Circu- Our hopes for further advancements in valvular heart dis- lation. 1983;68:891-896. ease are summarized in Table 5. 28. Roy SB, Gopinath N. Mitral stenosis. Circulation. 1968;38(suppl V):68-76. 29. Hickey MSJ, Blacksone E, Kirklin JW, et al. Outcome probabilities References after surgical commissurotomy: implication for balloon commissurot- 1. Luderitz B. Book review. N Engl J Med. 2002;347:2175. omy. J Am Coll Cardiol. 1991;17:29-42. 2. LeRoy F. A Century of Nobel Prize Recipients, Chemistry Physics and 30. Rahimtoola SH, Durairaj A, Mehra N, Nuno I. Current evaluation and Medicine. 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