Eur J Cardiothorac Surg 1999;16:524-532
© 1999 Elsevier Science NL
Surgical treatment of oligosymptomatic mitral valve incompetence?
C.F. Vahl,
T. Kloss,
Y. Yang,
M. Castell,
A. Mehrkens,
R. deSimone,
L. Schäffer,
S. Hagl
Department of Cardiac Surgery, University of Heidelberg, 69120 Heidelberg, Germany
Corresponding author. Tel.: +49-6221-566-128; fax: +49-6221-565-585
e-mail: christian_vahl{at}krzmail.krz.uni-he
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Abstract
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Objective: Despite improvements of the surgical technique in NYHA (III)–(IV) mitral valve incompetence (MVI) postoperative long-term results remain poor. As long-term results reflect primarily the ventricular function rather than the quality of the surgical technique the contractile performance of isolated papillary muscles obtained from patients undergoing mitral valve replacement for MVI (n=25) was analysed in detail. Methods: Muscle preparations (0.4x5.0 mm) obtained from left ventricular papillary muscles (NYHA (I), n=4; NYHA (II), n=7; NYHA (III), n=8; NYHA (IV), n=6) were loaded for intracellular calcium measurements with FURA-2, stretched to optimal length (Lmax) and electrically stimulated with frequencies ranging from 30 to 180 beats/min (b.p.m.) (10% above threshold, 37°C, Krebs–Henseleit solution). Isometric force development and diastolic intracellular calcium (measured by the ‘ratio method’; excitation light: wavelengths alternating 340 and 380 nm, frequency: 250 Hz) were simultaneously recorded as a function of the stimulation frequency. Results: At 60 b.p.m. force development was significantly higher in NYHA(I) myocardium (21.3±2.8 mN/mm2) than in NYHA(III) myocardium (12.8±2.2 mN/mm2), (P<0.0001). In NYHA(I) myocardium force rose with increasing stimulation frequency (‘positive staircase’). In contrast the stimulation frequency associated with maximum force was shifted towards lower frequencies in NYHA (II)–(IV) myocardium (‘negative staircase’). As compared with NYHA (I) myocardium diastolic intracellular calcium was significantly elevated at 150 b.p.m. in NYHA (II)–(IV) myocardium (P<0.01). Conclusion: The data show, that severe impairment of contractile function (‘negative staircase phenomenon’, reduced force, elevated diastolic calcium) is present in MVI classified as NYHA (III)–(IV) that may explain the poor long-term results. Most interestingly the data argue for a significant impairment of myocardial function even in NYHA(II) MVI. The results suggest an early surgical treatment of mitral valve incompetence as long as the myocardial function is normal (NYHA (I)) as (1) a reduced perioperative risk, (2) improved long-term results, and (3) a higher probability for mitral valve repair (instead of replacement) may be expected in these early stages of mitral valve disease.
Key Words: Mitral valve imcompetence • Surgery • Force frequency relationship • Calcium, FURA-2
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1. Introduction
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Despite improvements of the surgical technique in NYHA (III)–(IV) mitral valve incompetence (MVI) postoperative long-term results remain poor. As long-term results reflect primarily the ventricular function rather than the quality of the surgical technique per se, the optimal timing of the surgical intervention appears to be a decisive aspect. Similarities of physiological parameters measured in isolated myocardium obtained from patients with NYHA-(IV) mitral valve incompetence and from patients transplanted for end stage dilated cardiomyopathy support this view [1].
The success of aggressive timing in valvular surgery is well documented by the significant improvement of long-term surgical outcome for patients operated upon for aortic valve regurgitation and aortic valve stenosis during the past 15 years [2–4]. According to Carabello, a major contribution to the improved prognosis was the adoption of the so-called ‘55-rule’ for asymptomtomatic patients: if a patient with aortic regurgitation has an echocardiographic left ventricular end-systolic dimension >55 mm or an ejection fraction <55% surgical treatment is suggested even for NYHA-(I) patients when these thresholds are approached [2,5]. Improved surgical techniques with effective intraoperative cardioprotection contributed to reduce the acute operative risk significantly while the insertion of haemodynamically excellent and durable prostheses decreased the incidence of reoperations and valve related complications. Any of these developments supported the aggressive timing of operations for aortic valve disease and lead to a successful long-term outcome in this patient population.
The degenerative nature of mitral valve incompetence, frequently combined with a stenotic component, often precludes preserving the native valve. Thus in NYHA (III) and NYHA (IV) degenerative mitral valve incompetence the insertion of a prosthetic valve has to be expected currently as the standard operative procedure. However, mitral valve replacement by a prosthetic valve is only an acceptable solution for the haemodynamic problem while it generates a number of new problems: thromboembolism, haemorrhage from anticoagulation, valve failure and endocarditis. Reversibility of pulmonary hypertension, of arrhythmias, of ventricular function and architecture is possible but not predictable [6]. Once a prosthesis is inserted, patients become candidates for prosthesis-related complications regardless of the type of prosthesis implanted and the surgical technique that had been applied. Thus, in contrast to the surgical treatment of asymptomatic patients with atrial septal defects, the perioperative surgical risk in the group of young asymptomatic patients without heart failure and without significant coronary artery disease but with a prosthetic aortic valve replacement is still at least 2–3%. Later on, on average, the risk of serious valve-related complications is about 1–2% per patient year and thus far from being negligible [4,5].
Can surgery in asymptomatic patients with mitral valve regurgitation be considered? An important aspect supporting such an approach could be the increased likelihood to preserve the natural valve, when the operation is performed in an early stadium of slowly developing mitral valve incompetence. However, are there any physiological parameters that could justify such an aggressive approach? Currently there is no animal model available for mitral valve incompetence, which would help to characterize the functional alterations of the myocardium during the transition from a lower up to a higher NYHA class. For that reason human myocardium was used for the present analysis.
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2. Methods
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2.1. Patients and muscle specimens
Left ventricular muscle preparations (0.4x5.0 mm) were obtained from papillary muscles (NYHA (I), n=4); NYHA (II), n=7, NYHA (III), n=8, NYHA (IV), n=6) from patients that underwent mitral valve replacement for chronic mitral valve incompetence. Microscopic examination of the mitral valves confirmed the rheumatic aetiology with fibrous contracture of leaflet tissue and calcification in all patients. Patients with coronary artery disease, myocardial infarction, cardiomyopathy and bacterial endocarditis were excluded from the study. The degree of mitral valve regurgitation was classified based on angiographic examination after direct injection into the left ventricle in all patients using a scale from I to IV. The extent of mitral valve regurgitation as classified by the cardiologist was (II)–(III), (III) or (III)–(IV) when the patient was accepted for operation. There was patient in this study with mitral valve incompetence classified as (IV). Although the patients were asymptomatic in the NYHA (I)-group the extent of mitral valve regurgitation was considerable in this group and classified as (II)–(III) in three patients and (III–IV) in one patient. There was no significant correlation between the extent of angiographic mitral valve incompetence and clinical symptoms.
The surgical aspects of tissue harvesting had already been described in detail [7,8]. After cross-clamping of the aorta ascendens and instillation of 4°C cold 2000 ml cardioplegic solution (Bretschneider's HTK-solution (composition in mM/l: NaCl, 15.0; KCl, 9.0; MgCl2·6H2O, 4.0; potassium hydrogen-2 ketoglutarate, 1.0; histidine–HCl·H2O, 180.0; tryptophan, 2.0; mannitol, 30.0; CaCl2, 0.015; osmolarity: 310 mOsm/l) via the aortic root the mitral valve was excised including the heads of the papillary muscles. The muscle preparations were transported in the same 4°C cold cardioplegic solution that was also used during the preparation process of the muscle preparations.
Exclusion criteria were additional ischaemic heart disease, additional congenital disease, additional valvular disease, obstructive cardiomyopathy and previous heart transplantation. Patients that shifted acutely into the symptomatic state (rupture of chordae, endocarditis, myocardial infarction etc.) were also excluded. The study was reviewed and approved by the Committee of Medical Ethics in Human Research of the University of Heidelberg.
2.2. Experimental set-up
The same experimental set-up (Scientific Instruments, Heidelberg, Germany) was used as in previous studies [7,8]. The muscle preparations were mounted between force transducer and vibrator in a 37°C oxygenated Krebs–Henseleit solution (KHS, composition (in mM): NaCl, 119.0; NaHCO3, 25.0; KCl, 4.6; KH2PO4, 1.2; MgSO4, 1.2; CaCl2, 1.3; glucose, 11.0; pH: 7.4; pO2 >500 mmHg). Then the fibres were electrically stimulated (1 Hz, amplitude: 10% above threshold, duration: 5 ms, mode: square wave, isometric measurements conditions) and stretched to the muscle length associated with the maximum twitch amplitude (Lmax). A time interval of 25–40 min was required to obtain steady state measurement conditions at Lmax and 1 Hz stimulation frequency in preparations that did not undergo the FURA-2 loading procedure.
2.3. Calcium measurements
Intracellular calcium measurements were performed using the fluorescent dye FURA-2/AM, as already described [8]. The small left ventricular papillary muscle preparations underwent a 140 min incubation in darkness in oxygenated 26°C KHS containing 5 µM FURA-2/AM (FURA-2AM; F-0888/Sigma). The non-cytotoxic detergent Cremophor EL (0.5%) (Cremophor; C-5135/SIGMA) and TPEN (N,N,N,'N'-tetrakis(2-pyridylmethyl)ethylenediamine; P-4413/SIGMA) was added to the incubation solution (0.43 mg TPEN/100 ml KHS) in order to improve the solubility of FURA-2/AM and increase the transmembraneous permeation. After rinsing with oxygenated KHS for 15 min at 37°C, the muscle preparation was mounted between vibrator and force transducer and stretched in a stepwise fashion up to Lmax (stimulation frequency: 1 Hz). After excitation at alternating wave lengths of either 340 nm or 380 nm at 250 Hz the fluorescence signal was recorded at 510 nm by a photomultiplier. After background fluorescence subtraction the ratio (R) of both FURA-2 fluorescence signals was monitored continuously. At the end of the experiments, the calibration of the calcium signal was carried out using in vivo tetanization for Rmax and rapid skinning for Rmin measurement as already described [8]. Movement artefacts were experimentally excluded by induction of stretches and releases (20% ML at Lmax) of the inactivated preparation and by rapid stretching of the activated preparation during afterloaded contractions while the calcium transient was recorded. The calcium transient remained unaffected under these conditions.
A time interval of 30–75 min was required to obtain steady state measurement conditions at Lmax and 1 Hz stimulation frequency in preparations that underwent the FURA-2 loading procedure. In order to minimize photobleaching effects only few qualitative calcium measurements were carried out during this equilibration period.
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2.4. Experimental series
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2.4.1. Series I
The isolated human left ventricular papillary muscle preparations were electrically stimulated with ascending frequencies ranging from 30 to 180 beats/min (b.p.m.). Isometric force development (systolic, diastolic, amplitude) and diastolic intracellular calcium were simultaneously recorded as a function of the stimulation frequency (Fig. 1). At the end of the experiment the muscle was stimulated for 10 min at 1 Hz. Then the preparation was rinsed with Krebs–Henseleit solution containing 10 µM verapamil for 5 min. In most preparations resting tension remained constant while in some preparation resting tension decreased slightly (up to 8%). However, there was no relationship with the NYHA-class of the patient.
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Fig. 1. Original recordings of force development (lower trace) and intracellular calcium (upper trace) in myocardium from a patient with NYHA (I) mitral valve incompetence. With increasing stimulation frequency force and intracellular calcium raise. Time scale: 100 ms=1 division; preparation: isolated human left ventricular papillary muscle.
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2.4.2. Series II
In control experiments the same measurements were carried out using isolated muscle specimen from the papillary muscle of the same patient but without previous FURA-2 loading.
2.5. Statistical analysis
The values for force and calcium of 10 subsequent twitches were averaged for calculation of absolute values for force and calcium data. In order to evaluate statistical significance between the various groups, one way statistical analysis of variance followed by Student's t-test was carried out. Mean values are presented as mean±SD For on line data analysis special software was used (Scientific Instruments, Heidelberg). A value of P<0.05 was considered to indicate a statistically significant difference.
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3. Results
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3.1. Force generation and intracellular calcium
At 60 b.p.m. force development was significantly higher in NYHA (I) myocardium (21.3±2.8 mN/mm2) than in NYHA (III) myocardium (12.8±2.2 mN/mm2), (P<0.0001). Passive resting force at Lmax was 5.0±0.4 mN/mm2 in NYHA (I), 6.5±0.7 mN/mm2 in NYHA (III) myocardium and increased up to 7.9.±0.6 mN/mm2 in NYHA (IV) myocardium.
In NYHA (I) myocardium force rose with increasing stimulation frequency (‘positive staircase’) up to an ‘optimal frequency’ (Fig. 2). This ‘optimal frequency’ that was associated with maximum force amplitudes was near 150 b.p.m. in NYHA (I) myocardium. In contrast the stimulation frequency associated with maximum force was shifted towards lower frequencies in NYHA (II)–(IV) myocardium (‘negative staircase’). In NYHA (II) myocardium the shape of the force-frequency relation is already completely different from that obtained in NYHA (I) myocardium (Fig. 3). The optimum frequency in NYHA (II) myocardium was between 90 and 120 b.p.m. In NYHA (III) myocardium the optimum frequency was near 90 b.p.m. and declined to an optimum between 60 b.p.m. in NYHA (IV) myocardium. The maximum force that the muscle preparation could generate at the optimal frequency declined regardless the frequency with increasing NYHA-classification. In NYHA (I) myocardium the maximum mean value of force development was measured at a frequency of 150 b.p.m. (33.1±4.0 mN/mm2) while the maximum value in NYHA (II) myocardium was measured at 120 b.p.m. (22.1±1.8 mN/mm2). This difference of force generation between NYHA (I) and NYHA (II) myocardium was significant (P<0.0001).
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Fig. 2. Force development as a function of stimulation frequency (ranging from 0.5 up to 3 Hz) in isolated myocardium obtained from a NYHA (II) mitral incompetence. With increasing stimulation frequency force development increases up to a maximum and then declines (positive staircase phenomenon). Note that resting force increases at higher stimulation frequencies.
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Fig. 3. Force development (active force in mN/mm2) is presented as a function of the stimulation frequency (beats per minute). Note, that in NYHA (IV) myocardium, force does not increase with increasing stimulation frequencies but declines (inverted, or negative force frequency relationship). Note, that the differences between the different NYHA-classes are severe.
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Diastolic steady state force remained nearly constant in NYHA (I) myocardium when the stimulation frequency increased. In contrast in NYHA (II)–NYHA (IV)-myocardium steady state diastolic force increased with increasing stimulation frequencies (Fig. 4).
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Fig. 4. Diastolic steady state force (‘resting tension’ in mN/mm2) is shown as a function of the stimulation frequency. Note that diastolic steady state force is not passive but increases with increasing stimulation frequencies especially in NYHA (II)–(IV) myocardium.
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The diastolic free intracellular calcium concentration increased with increasing stimulation frequencies regardless the NYHA-class of the patient (Fig. 5). However, the slope of the increase became steeper with increasing NYHA-class. As compared with NYHA (I) myocardium diastolic intracellular calcium was significantly elevated at 150 b.p.m. in NYHA (II)–(IV) myocardium (P<0.01) (Fig. 6).
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Fig. 5. Original recordings showing simultaneous registrations of intracellular calcium and force development in a muscle preparation obtained from a patient with NYHA (IV) mitral valve incompetence. Note that diastolic intracellular calcium raises dramatically while the force frequency relationship is inverted.
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Fig. 6. Diastolic calcium (in nM) is presented as a function of the stimulation frequency. Note the important differences of intracellular calcium metabolism in the different NYHA-classes. For frequencies >90 b.p.m. the differences between NYHA (I) and NYHA (IV) are significant.
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3.2. Control measurement without FURA-2 loading
The mean values for developed force at 1 Hz and optimal length were 5–15% higher in preparations that did not undergo FURA-2 loading in all preparations regardless the NYHA-class of the patients. These differences failed to be significant (data not shown). The shape of the force frequency relation was qualitatively the same in control preparations. The amplitudes of active force generation had a tendency to be higher in control myocardium without FURA-2 loading. However at the given number of observations in any of the NYHA-classes none of these differences was statistically significant at the P<0.05 level.
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4. Discussion
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The most important finding of the present study is that the data clearly reveal that severe alterations of the contractile function (negative staircase phenomenon, reduced force development, increased resting tension, elevated diastolic calcium) are present in isolated human myocardium obtained from left ventricular myocardium of patients operated upon for mitral valve incompetence classified as NYHA (III)–(IV). The results provide an additional pathophysiological basis that helps to understand the poor long-term results observed after mitral valve replacement in end stage mitral valve regurgitation.
It was a surprizing result that the data indicate a significant impairment of myocardial function even in isolated myocardium obtained from patients classified as NYHA (II). Characteristic alterations of the force frequency relation and the intracellular calcium metabolism were already present in isolated myocardium obtained from NYHA (II) mitral valve incompetence (Fig. 3).
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4.1. Pathophysiological aspects
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4.1.1. Resting tension
Resting tension has a passive and active component as illustrated by the changes of diastolic resting force in Fig. 4 and diastolic intracellular calcium in Fig. 6. However, at 1 Hz stimulation frequency resting tension was supposed to be passive as indicated by missing effects calcium antagonists on resting force. Thus the increased resting force at Lmax and 1 Hz stimulation frequency in NYHA (III) and (IV) myocardium cannot be related to alterations of the intracellular calcium handling.
An increased passive resting force required to obtain Lmax corresponds to increased diastolic stiffness and had been described in isolated trabeculae of patients transplanted for end stage heart failure by previous investigators [7,9]. A simple explanation could be that, optimal length (Lmax) required longer sarcomere-lengths in failing than in normal myocardium. According to this hypothesis a higher degree of stretching should be expected to obtain optimal length this way, explaining the presence of increased diastolic stiffness. However, in previous studies on skinned human myocardium obtained from end stage heart failure and from patients operated upon for mitral valve disease the sarcomere length, required for the generation of maximum force, was the same in failing and normal human myocardium (near 2.2 µm) [7,10] and in different types of mitral valve disease [11]. In addition the observation of DelMonte et al. [12] who found that the sarcomere lengths of isolated myocytes obtained from human myocardium did not differ as a function of the NYHA class argues against this explanation. For all these reasons, we believe that an increased presence of perimysial and endomyosial fibrosis in failing myocardium [11,13,14] or potential changes in the structure of titin [15] are more likely to explain the increasing diastolic stiffness in increasing MVI NYHA classes. An increasing proportion of collagenous tissue within the muscle includes, that at a given diameter the percentage of sarcomeres has to be reduced. This is consistent with the decreased extent of active force generation.
4.1.2. Force frequency relation
The alterations of the force frequency relationship had been established as an important physiological parameter to distinguish between normal and failing myocardium [16]. According to the current knowledge these alterations of the force frequency do mainly correspond to alterations of the intracellular calcium metabolism.
Similarly, as in normal myocardium, increasing stimulation frequencies are associated with increasing intracellular calcium amplitudes in NYHA (I) MVI myocardium. Increasing amplitudes of force generation reflect increasing amplitudes of the intracellular calcium transient. However, increased amplitudes of the calcium transient require a greater amount of calcium reuptake into the sarcoplasmic reticulum (SR). As this is an energy consuming process the energy costs for electromechanical coupling should increase with increasing intracellular calcium levels and correspondent increasing force amplitudes. This is consistent with observations of Alpert et al. [17] that in rat papillary muscle tension independent heat decreased by 22±4% when the amplitude of active force generation was reduced an 11% reduction of the muscle length. Regardless how the calcium enters the cytosol, the elimination of calcium from the cytosol is retarded in failing human myocardium [16,18–20]. As the calcium reuptake rate into the SR is reduced in myocardium obtained from patients with high NYHA classes, the increased diastolic calcium levels at higher stimulation frequencies are most likely related to an altered calcium handling. The increased diastolic calcium levels observed at higher stimulation frequencies reflect a persisting level of activation during the diastolic period. This explains the increased passive diastolic force at higher stimulation frequencies. However, ‘passive resting force’ has a clearly active component [10] which suggests, that diastolic stiffness is not constant but depends also on physiological parameters such as the intracellular calcium metabolism.
4.2. Clinical aspects
The present data clearly reveal, that the transition from normal towards failing myocardium had already begun in NYHA (II) myocardium obtained from patients undergoing valve surgery for mitral valve incompetence. However, it is not known whether these alterations are reversible and, if yes, to what extent reversible. Furthermore it is not known, how rapidly these pathophysiological alterations progress. In the literature there are currently neither haemodynamic nor demographic factors available that could predict which patients will eventually change within what time interval to the symptomatic status.
Only few NYHA (I) MVI-patients are likely to progress rapidly as mitral valve incompetence is a slowly developing disease. For that reason one could argue, that – despite the clear pathophysiological findings of the present study – an aggressive approach towards a surgical intervention has not to be contemplated. According to this current line of argumentation aggressive surgery would protect only few patients from progressing rapidly from the asymptomatic to the symptomatic status while many patients would be operated upon ‘needlessly’. However, in fact there is no sharp borderline between asymptomatic and NYHA (II) patients, that allows such a clear cut decision, and that could provide a rational basis for an optimal timing of the surgical intervention. Thus the argument that the operative repair is only indicated immediately before transition to the symptomatic state is quite theoretical and does not reflect the clinical situation. There is a slow and continuos progression of the disease and of the pathophysiological alterations and not a ‘jump’ from the asymptomatic to the symptomatic class. This clinical view is clearly supported by the present analysis that shows a progression of the pathophysiological alterations with increasing NYHA-class.
Thus, as no haemodynamic nor demographic data are available that predict the change from the asymptomatic to the symptomatic state the present strong pathophysiological findings require careful reconsideration: the present study clearly shows, that the contractile properties of the myocardium are already severely altered once the patient had become symptomatic. These altered contractile properties have to be added to alterations of the left ventricular architecture and additional extracardial changes occurring during the natural course of mitral valve incompetence. As these changes are severe and in the last stadium very similar to those observed in end stage dilated cardiomyopathy the transition to the symptomatic state has to be avoided.
The current standard practice in the treatment of NYHA (I) mitral valve incompetence consists in medical treatment with diuretics and if the patients are in atrial fibrillation with diuretics, warfarin and digoxin until the symptomatic status progressed past New York Heart Association classification II or III. As sudden death is extremely rare in mitral valve regurgitation there had been little arguments for operating asymptomatic patients. However, even in the clinical practice the knowledge that an asymptomatic patient has severe mitral valve regurgitation as classified by echo-Doppler analysis creates already a problem: both, patient and physician may become uncomfortable with a strategy of watchful waiting, as intermittent atrial fibrillation is associated with the risk cerebral emboli and anticoagulation with the risk of haemorrhage. The unknown velocity of progression may also heighten the patient's anxiety about unwanted sequelae that may be avoided by early invasive treatment. It is well known that surgery for mitral valve incompetence had become substantially less invasive during the last decade with an increasing proportion of patients with valve reconstruction and an improved management of extracorporeal circulation. For that reason in asymptomatic patients operative mortality can be expected to be similar to patients with asymptomatic atrial septal defect.
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4.3. Arguments for an operation of NYHA (I) MVI-patients
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The pathophysiological data of the present study strongly support an early timing of surgical treatment of mitral valve incompetence as long as the myocardial function is normal (NYHA (I)). Additional arguments for an aggressive approach are: (1) a reduced perioperative risk; (2) improved long-term results; and (3) a higher probability for mitral valve repair (instead of replacement) can be expected in these early stages of mitral valve disease.
Asymptomatic patients with mitral valve regurgitation do not die suddenly. Thus the suggestion of a surgical intervention has to offer clear benefits for the asymptomatic NYHA (I) patient with mitral valve incompetence. We believe, that if intermittent atrial fibrillation occurs, if pulmonary hypertension begins to develop, if a systemic embolus was present and if preoperative echocardiography combined with 4D-visualization of the valve and of the jet seem to indicate that the valvular anatomy is suitable for a successful surgical intervention, a surgical intervention has to be seriously considered. The surgical intervention in these patients would not only have prophylactic character but is beneficial as the development of endocarditis, embolism, chronic atrial fibrillation and heart failure is prevented. It helps to avoid the development of myocardial dysfunction. In addition even on the long run the mitral valve replacement may be avoided only by an early timing of the surgical intervention. The balloon valvuloplasty in asymptomatic patients with mitral valve stenosis was based on similar arguments [21–23].
Even in asymptomatic patients without additional clinical signs for the presence of developing mitral valve incompetence (no atrial fibrillation, embolus etc.) a surgical approach has to be seriously considered. The progression of valvular degeneration induced by pathologic flow dynamics, the changes of ventricular architecture and the alterations on the contractile machinery can be only avoided by an early operation. Considerable myocardial impairment is already present in NYHA (II) mitral valve incompetence. Currently no data on muscle fibre level are available that indicate, whether these alterations are reversible after mitral valve replacement or whether this myocardial component will contribute to the long-term results after mitral valve replacement. However, the poor clinical results after mitral valve replacement in NYHA (III) and (IV) patients seem to indicate that myocardial dysfunction is apparently not reversible in end stage mitral valve incompetence.
However, the present study was not designed to answer the question, whether prophylactic surgery can save lives but to analyse, whether there are pathophysiolgical arguments for an aggressive surgical approach.
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4.4. Are we ready for prophylactic surgery?
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Analysing this question, we wish to stress six aspects that may be important for the realization in clinical practice. (1) Is the operative risk less than 1%? (2) Can an effective haemodynamic and anatomical reconstruction be guaranteed and can suitable valves for surgery be preoperatively identified? (3) Is intraoperative 3D and 4D visualization and reconstruction of atrial and ventricular morphology introduced to allow a well controlled rational planing, performance and control of the operative procedure? (4) Is intraoperative 3D and 4D visualization of transvalvular flow dynamics performed to evaluate the operative result? In addition to these questions we like to mention two further questions, that may further support the acceptance of prophylactic surgery. (5) Is there a suitable minimal invasive technique. (6) Are robotic and computer assisted methods useful in order to help to reduce potential ‘human errors’ towards a minimum?
If the operative risk would clearly and constantly be less than 1% and the natural valve could be preserved in all patients by using new intraoperative diagnostic tools (visualization) and optimized surgical techniques (robotic and computer assisted surgery), the strong pathophysiological data presented are an important argument to justify an aggressive prophylactic approach to surgery.
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4.5. Limitations and methodological aspects
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The criteria to form different NYHA-classes of patients with mitral valve incompetence are clinical criteria and to some extent subjective. It had recently been stressed, that these clinical criteria may not be sufficient to characterize myocardial performance properly [24]. In the same NYHA (I) group there are patients with a mitral valve incompetence graded from echocardiographic findings as MVI-grade 1 up to MVI-grade 3. Despite these limitations there is currently no alternative generally accepted classification available. The present data seem to indicate, that the different NYHA classes can distinguish between different myocardial performance as they were in fact associated with different contractile behaviour on the isolated muscle fibre level. However, it had to be stressed that appearance of symptoms indicate the failure of all compensatory mechanisms. For that reason the simple distinction between symptomatic and asymptomatic patients does not reflect the pathophysiology of mitral valve incompetence properly. Many NYHA (II) patients already have a long history of mitral valve incompetence.
Chemical loading with FURA-2/AM results in compartmentalization into intracellular organelles. Despite the short loading procedure, endothelia-free preparations and minimal exposure to fluorescent light it is difficult to exclude this potential measurement artefact completely. However, the similarity of the intracellular calcium transient recorded after FURA-2 microinjection and after loading with FURA-2/AM as observed by Backx and Ter Keurs [25] indicates that careful experimental handling may keep this factor small. Photobleaching effects [26] were minimized by selecting a minimal light intensity by limiting the illumination to the brief recording periods. In comparison to the microinjection technique it appears to be an advantage of the chemical loading procedure, that potential damage of the preparation, alterations of membrane properties (e.g. leaking), electrophysiological changes of the membrane potential and artificial injection into intracellular organelles are avoided. Despite several well known limitations of the chemical loading procedure [8,10,26] preservation of cell integrity was an important argument for the selection of the chemical loading procedure in the present study. Although in vivo and in vitro FURA-2 calibration curves were similar [25] caution is still suggested regarding the absolute values of the calculated calcium concentrations under the given experimental and loading conditions [8].
The interpretation of intracellular calcium transients as estimated by the FURA-2 ratio method and their relation to mechanical performance requires caution. Although the mechanical performance of preparations with and without FURA-2 loading was not statistically different in the present study, the data had a wide dispersion about the mean and it can not be excluded, that a statistical difference would be born out with a much larger number of observations. In rat trabeculae Backx and ter Keurs [25] had found that FURA-2 loading reduced the force amplitude and altered the kinetic properties. However, these potential negative inotropic effects of FURA-2 loading per se are present in any preparation of any group and should not affect the differences between the preparations from myocardium obtained from different NYHA classes.
Summarizing the present data provide an additional rational basis supporting an aggressive time of the surgical intervention in mitral valve incompetence supposed the operative risk is less than 1% and the natural valve could be preserved in nearly all patients. Application of new intraoperative diagnostic tools and optimized surgical techniques may support this surgical approach essentially. Considering the present data the only question that remains is, whether cardiac surgery is already ready for prophylactic operations.
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Acknowledgments
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This study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, SFB 414, research projects H4 (CFV) and H1 (RdS). Dr Yang from the University Dalian, China, received a research grant from the SFB 414. The authors wish to thank Anne Schuppe, Karin Sonnenberg and Nicole Stumpf for their expert experimental assistance.
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Footnotes
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Presented at the 12th Annual Meeting of the European Association for Cardio-thoracic Surgery, Brussels, Belgium, September 20–23, 1998.
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Appendix A
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Conference discussion
Dr G. Dreyfus (Suresnes, France): I would just like to remind you that we had presented 2 years ago at the AATS in San Diego 185 mitral valve repair in asymptomatic patients, Class I and II patients, that we clearly showed that irrespective of their functional class, some patients have very dilated hearts and the only indications should be the grade of mitral regurgitation greater than 3 plus, and therefore I fully agree with what you say, and you can achieve in such a series of patients a mortality lower than 1%.
Dr Vahl: We agree completely with your argument, we know your study, and there is another interesting example of a similar problem in the history. In patients with atrial septal defect (ASD) we had a mortality of about 6% when it was operated upon in the last stage (NYHA (III)–(IV)), and now when asymptomatic patients are operated upon, the mortality is, as well, far less than 1%.
Dr L. Cohn (Boston, MA, USA): It is a little confusing sometimes when you say that somebody with mitral incompetence is functional Class I because in fact they may have no symptoms, but, as the previous discussant alluded to, the patient's ventricular function may be absolutely terrible. How do you correlate this in terms of the data that you presented to us?
Dr Vahl: This is in fact an important question as it leads to the problem of an inadequate preoperative classification. We know the problems of the classification according to the New York Heart Association and there is a review of Clark who stresses this problem as well. However, currently there is no additional and better classification available. The transition from the asymptomatic to the symptomatic class is no marker for changes of myocardial function but also indicates that the compensatory mechanism begin to fail. And this is another point that argues for treatment of mitral valve disease as soon as this disease is detected, and that watchful waiting could not be a good strategy.
Dr P. Kalmar (Hamburg, Germany): Your significant paper demonstrates how important the early operations are. Do you have any information about the time period until an acquired mitral insufficiency begins to cause symptoms. I mean not only in regard to reduced work load capacity but also in terms of first organic cardiac alterations (i.e. reduction of stoke volume, cardiac output, increase of pulmonary resistance etc.)?
In symptom-free patients I would suggest operating only under the restriction, that the risk should be below 1% and the changes of repairing and saving the native valve are correspondingly excellent. The reason for this conservative standpoint is based on the fact, that nowadays echocardiographies show a mitral regurgitation more often in patients without any symptoms who stay stabilized for a long period of time.
Dr Vahl: We looked for such a classification but at least we did not find any demographic data nor any haemodynamic data that could predict the transition from the NYHA Class (I) to the NYHA Class (II) in mitral valve incompetence. We did only find data regarding the aortic valve stenosis where there was the 55% rule of Carabello, for example, but in mitral valve disease we didn't find anything. Of course one could argue if arrhythmias are present or systemic emboli are present and so on, then it is time for an operation, but this is not documented.
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Received November 10, 1998;
received in revised form June 14, 1999;
accepted June 22, 1999.
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Abstract
1. Introduction
