Timing of valve replacement in aortic stenosis. Moving closer to perfection.
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Aortic Valve Stenosis↗
Biomedical subjects
B A Carabello
Publications and source records attributed to B A Carabello.
Premorbid determinants of left ventricular dysfunction in a novel model of gradually induced pressure overload in the adult canine.
BACKGROUND: When a pressure overload is placed on the left ventricle, some patients develop relatively modest hypertrophy whereas others develop extensive hypertrophy. Likewise, the occurrence of contractile dysfunction also is variable. The cause of this heterogeneity is not well understood. METHODS AND RESULTS: We recently developed a model of gradual proximal aortic constriction in the adult canine that mimicked the heterogeneity of the hypertrophic response seen in humans. We hypothesized that differences in outcome were related to differences present before banding. Fifteen animals were studied initially. Ten developed left ventricular dysfunction (dys group). Five dogs maintained normal function (nl group). At baseline, the nl group had a lower mean systolic wall stress (96 +/- 9 kdyne/cm2; dys group, 156 +/- 7 kdyne/cm2; P < .0002) and greater relative left ventricular mass (left ventricular weight [g]/body wt [kg], 5.1 +/- 0.36; dys group, 3.9 +/- 0.26; P < .02). On the basis of differences in mean systolic wall stress at baseline, we predicted outcome in the next 28 dogs by using a cutoff of 115 kdyne/cm2. Eighteen of 20 dogs with baseline mean systolic stress > 115 kdyne/cm2 developed dysfunction whereas 6 of 8 dogs with resting stress < or = 115 kdyne/cm2 maintained normal function. CONCLUSIONS: We conclude that this canine model mimicked the heterogeneous hypertrophic response seen in humans. In the group that eventually developed dysfunction there was less cardiac mass despite 60% higher wall stress at baseline, suggesting a different set point for regulating myocardial growth in the two groups.
Animals↗
Aortic regurgitation in women. Does the measuring stick need a change?
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Aortic Valve Insufficiency↗
Translational initiation factor eIF-4E. A link between cardiac load and protein synthesis.
To define the coupling mechanism between cardiac load and the rate of protein synthesis, changes in the extent of eIF-4E phosphorylation were measured after imposition of a load. Electrically stimulated contraction of adult feline cardiocytes increased eIF-4E phosphorylation to 34% after 4 h, as compared with 8% phosphorylation in quiescent controls. However, eIF-4E phosphorylation did not increase upon electrical stimulation in the presence of 7.5 mM 2,3-butanedione monoxime, an inhibitor of actin-myosin cross-bridge cycling and active tension development. Treatment of adult cardiocytes with either 0.1 microM insulin or 0.1 microM phorbol 12-myristate 13-acetate increased eIF-4E phosphorylation to 23 and 64%, respectively, but these increases were not blocked by 2,3-butanedione monoxime. In canine models of acute hemodynamic overload in vivo, eIF-4E phosphorylation increased to 23% in response to left ventricular pressure overload as compared with 7% phosphorylation in controls. Acute volume overload had no effect on eIF-4E phosphorylation. These changes in eIF-4E phosphorylation account for differences in anabolic responses to acute pressure versus acute volume overload. These data suggest that eIF-4E phosphorylation is a mechanism by which increased cardiac load is coupled to accelerated rates of protein synthesis.
Animals↗
Models of volume overload hypertrophy.
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Animals↗
Management of valvular regurgitation.
The principles of the management of left-sided valvular regurgitation, which weigh watchful waiting against surgery, have crystallized over the past 15 years. While the timing of surgery once was enigmatic, it is now clear that surgery must be done prior to the development of prolonged left ventricular dysfunction. Fortunately, satisfactory indexes have been developed that allow the clinician to detect and avoid such dysfunction. Therefore, patients now undergo surgery sooner, resulting in reduced operative mortality and better long-term survival. However, there are still several unresolved issues regarding the management of valvular regurgitation. For instance, operations for mitral regurgitation that preserve the mitral apparatus improve postoperative left ventricular performance compared with conventional mitral valve replacement. However, the proper timing for these operations is still being examined. Another issue is whether vasodilators, which reduce the regurgitant overload, can delay the onset of ventricular dysfunction and thus also delay surgery. In contemplating vasodilator use there is a paradox between the principle of early surgery to prevent dysfunction and use of medical therapy to delay surgery. Several studies which have appeared in the literature in the past year help resolve some of these issues.
Aortic Valve Insufficiency↗
Indications for valve surgery in asymptomatic patients with aortic and mitral stenosis.
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Aortic Valve Stenosis↗
The relationship of left ventricular geometry and hypertrophy to left ventricular function in valvular heart disease.
Valvular heart disease imposes a hemodynamic load on the left or right ventricle. This load is compensated by the development of ventricular hypertrophy. The pattern of hypertrophy which develops is characteristic of each type of valvular lesion with concentric hypertrophy compensating the pressure overload of aortic stenosis, eccentric hypertrophy compensating the volume overload of mitral regurgitation and both concentric and eccentric hypertrophy compensating the combined pressure and volume overload of aortic regurgitation. While these patterns are characteristic, there is substantial variation in the geometric distribution of hypertrophy among individuals with the same valvular disease. This variability in turn produces variability in the amount of compensation from patient to patient. The geometric pattern of hypertrophy which develops primarily affects left ventricular function as it relates to the Laplace equation. An increase in the radius to thickness ratio increases wall stress while a decrease in this ratio decreases wall stress. Discussed below are the mechanisms by which the various geometries that develop in valvular heart disease affect loading to become adaptive or maladaptive or both.
Aortic Valve Insufficiency↗
Therapy for mitral stenosis comes full circle.
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Catheterization↗
Native beta-adrenergic support for left ventricular dysfunction in experimental mitral regurgitation normalizes indexes of pump and contractile function.
BACKGROUND: It is generally accepted that the adrenergic nervous system provides inotropic support for the failing heart. However, the magnitude of this support has never been studied extensively. The present study was performed to test the hypothesis that the adrenergic nervous system is capable of maintaining indexes of pump and contractile function in the normal range despite significant innate myocardial depression. METHODS AND RESULTS: We used our model of experimental canine mitral regurgitation, which produces left ventricular dysfunction after 3 months of volume overload. We studied indexes of contractile function on and off beta-blockade at baseline and again on and off beta-blockade 3 months after chronic mitral regurgitation had induced significant contractile dysfunction. At baseline, acute beta-blockade caused insignificant reductions in the mass-corrected slope of the end-ejection stress-volume relation (EESVR), the end-systolic stiffness constant, and the ejection fraction-end-systolic stress and the mean velocity of circumferential fiber shortening (VCF)-end-systolic stress relations. After 3 months of chronic mitral regurgitation, all indexes of contractile function were normal in the unblocked state except for the VCF-stress relation, which was mildly reduced. However, after acute beta-blockade after 3 months of chronic mitral regurgitation, the EESVR fell to 303 +/- 27 versus 443 +/- 24 during acute beta-blockade before mitral regurgitation was created (P < .05), and the end-systolic stiffness constant was reduced to 2.54 +/- 0.15 versus 3.27 +/- 0.11 (P < .05). Only after beta-blockade was the ejection fraction-stress relation significantly reduced for dogs with chronic mitral regurgitation. The VCF-stress relation became markedly more abnormal. The viscosity-velocity relation of myocytes isolated from the ventricles of the dogs with mitral regurgitation confirmed that substantial innate contractile depression was present. CONCLUSIONS: After 3 months of chronic mitral regurgitation, the adrenergic nervous system was able to maintain most indexes of contractile function in the normal range despite significant depression in innate contractile function. Thus, in the absence of beta-blockade, significant innate contractile depression may be obscured by adrenergic support.
Animals↗
Acute changes in myosin heavy chain synthesis rate in pressure versus volume overload.
The left ventricular hypertrophy that develops with the volume overload of mitral regurgitation is relatively less than that which develops with the pressure overload of aortic stenosis even when both lesions are severe. The hypertrophy that develops must be the sum of changes in the rate of myocardial protein synthesis and degradation. In the present canine study, we explored early changes in the synthesis rate of myosin heavy chain in response to severe acute pressure overload versus that of the severe acute volume overload of mitral regurgitation. We tested the hypothesis that in acute overload, the rate of protein synthesis would increase less in the volume-overload model than in the pressure-overload model, a potential partial mechanism for the discrepancy in the eventual total amount of hypertrophy that develops in these two lesions. Acute pressure overload was produced by inflating a balloon in the descending aorta, and acute volume overload was produced by using our closed-chest mitral chordal rupture technique. In both models, the hemodynamic lesion that was created was severe. In eight dogs with pressure overload, the average gradient across the balloon was 119.8 +/- 6.1 mm Hg. In six dogs with volume overload, the average regurgitant fraction was 0.67 +/- 0.06. Six other dogs served as controls. The average rate of myosin heavy chain synthesis in control dogs was 2.7 +/- 0.2% per day, virtually identical to the rate we found in the severe volume-overload model. In contrast, the rate was increased in the pressure-overload model by 30% to 3.5 +/- 0.3% per day (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation.
The mechanism by which beta blockade improves left ventricular dysfunction in various cardiomyopathies has been ascribed to improved contractile function of the myocardium or to improved beta-adrenergic responsiveness. In this study we tested two hypotheses: (a) that chronic beta blockade would improve the left ventricular dysfunction which develops in mitral regurgitation, and (b) that an important mechanism of this effect would be improved innate contractile function of the myocardium. Two groups of six dogs with chronic severe mitral regurgitation were studied. After 3 mo both groups had developed similar and significant left ventricular dysfunction. One group was then gradually beta-blocked while the second group continued to be observed without further intervention. In the group that remained unblocked, contractile function remained depressed. However, in the group that received chronic beta blockade, contractile function improved substantially. The contractility of cardiocytes isolated from the unblocked hearts and then studied in the absence of beta receptor stimulation was extremely depressed. However, contractility of cardiocytes isolated from the beta-blocked ventricles was virtually normal. Consistent with these data, myofibrillar density was much higher, 55 +/- 4% in the beta-blocked group vs. 39 +/- 2% (P < 0.01) in the unblocked group; thus, there were more contractile elements to generate force in the beta-blocked group. We conclude that chronic beta blockade improves left ventricular function in chronic experimental mitral regurgitation. This improvement was associated with an improvement in the innate contractile function of isolated cardiocytes, which in turn is associated with an increase in the number of contractile elements.
Adrenergic beta-Antagonists↗
The effects of complete versus incomplete mitral valve repair in experimental mitral regurgitation.
Severe mitral regurgitation (regurgitant fraction 0.75 +/- 0.02) was created in eight dogs by our closed-chest chordal rupture technique. After 3 months of chronic mitral regurgitation all indices of contractile function were depressed. Mitral valve repair was then attempted. Postoperative regurgitant fraction was reduced compared with the preoperative value in all eight dogs. Concomitantly, forward cardiac output increased in all dogs and pulmonary capillary wedge pressure fell in all dogs. However, in some dogs, significant regurgitation persisted despite repair. Postoperative regurgitant fraction ranged from 0% to 60%. Postoperative residual regurgitant fraction was related significantly to postoperative cardiac output (r = 0.99), pulmonary capillary wedge pressure (r = 0.77), ejection fraction (r = 0.75), and two indices of contractile function--the mass-corrected end-systolic stress volume relationship (r = 0.87) and end-systolic stiffness (r = 0.93). In general, these parameters returned to their normal values before mitral regurgitation when postoperative regurgitant fraction was less than 30%. Myocytes isolated from the ventricles at the end of study also demonstrated normal contractile function when regurgitant fraction was less than 30%.
Animals↗
Effect of catheter positioning on the variability of measured gradient in aortic stenosis.
The purpose of this study was to quantify the variation in measured aortic valve gradient and calculated aortic valve area when different techniques of cardiac catheterization were utilized. Hemodynamic assessment of aortic stenosis severity requires an accurately determined pressure gradient. In aortic stenosis, the presence of intraventricular pressure gradients and downstream pressure recovery within the aorta means that a range of aortic valve gradients could be measured in a given patient depending upon catheter position and measurement technique. To quantify the degree of variation in measured gradient and calculated aortic valve area, we generated transvalvular gradients by nine different techniques in 15 patients (11 men, 4 women; 29-86 years old). Patients were divided into those with severe aortic stenosis (aortic valve area < or = 0.6 cm2, n = 6) and those with moderately severe aortic stenosis (aortic valve area 0.61-0.90 cm2, n = 9). Considerable variation in measured gradient and calculated aortic valve area was observed. The maximum variation in gradient was similar in severe and moderately severe aortic stenosis groups (33 mm Hg. vs. 32 mm Hg., p = NS). However, the variation in gradient as a percent of maximum gradient was greater (P < 0.05) in the moderately severe aortic stenosis group. The maximum variation in calculated aortic valve area was 0.1 cm2 in the severe group and 0.3 cm2 in the moderately severe group (P < 0.01). An intraventricular gradient, present in 13 of 15 (87%) patients, was partially responsible for the variation in pressure gradient measurement and calculated aortic valve area.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Cardiocyte contractile performance in experimental biventricular volume-overload hypertrophy.
Previous studies have shown that the right ventricle (RV) appears to tolerate volume overloading better than does the left ventricle (LV). To determine whether this dichotomous response is due to intrinsic differences in the contractile performance of volume hypertrophied RV vs. LV cardiac muscle cells, or cardiocytes, we characterized the contractile performance of cardiocytes isolated from an experimental feline model of biventricular volume overload (n = 7 cats), wherein a peripheral arteriovenous fistula (AVF) produced an identical duration and degree of volume overload for both ventricles; sham-operated cats served as the appropriate controls (n = 7). Cardiocyte contractile function was defined by laser diffraction measurement of sarcomere motion. For the AVF cats, there was a 2.4-fold increase in cardiac output, a significant increase in the RV and LV weight-to-body weight ratios, and a significant increase in cell surface area for the RV and LV cardiocytes. Despite this, cardiocyte contractile function in the AVF cats was entirely normal. Thus there was no significant difference between RV and LV cardiocytes from control cats in the extent or velocity of sarcomere shortening either in 1 cP superfusate or in higher viscosity superfusates, and comparison of RV and LV cells from the AVF cats to those from sham-operated cats again revealed no significant differences. Furthermore, cardiocyte relengthening properties showed no significant differences between AVF and control groups. In summary, this study shows that contractile dysfunction is not an inherent property of either RV or LV cardiac muscle cells hypertrophying in response to substantial volume overloading when preload is increased but afterload is normal.
Animals↗
Changes in diastolic function during development and correction of chronic LV volume overload produced by mitral regurgitation.
BACKGROUND: Mitral regurgitation (MR) causes an augmentation in left ventricular (LV) diastolic function, increasing early diastolic filling rate and decreasing LV stiffness. Whether these changes in diastolic function persist, return to normal, or become abnormal after mitral valve replacement (MVR) is unknown. METHODS AND RESULTS: Simultaneous LV echocardiography and catheterization studies were performed in six dogs in the baseline state (baseline), 3 months after creation of MR (chronic MR), and 3 months after MVR. Chronic MR caused LV dilation (end-diastolic dimension increased from 4.5 +/- 0.1 cm in baseline to 5.8 +/- 0.1 cm in chronic MR, p < 0.05) and eccentric LV hypertrophy (LV-to-body weight ratio increased from 3.6 +/- 0.2 g/kg in baseline to 4.9 +/- 0.4 g/kg in chronic MR, p < 0.05). Chronic MR caused an increase in LV early diastolic filling rate (peak rate of increase in minor-axis dimension increased from 11 +/- 1 cm/sec in baseline to 18 +/- 1 cm/sec in chronic MR, p < 0.05), did not change the time constant of myocardial relaxation (tau was 31 +/- 4 msec in baseline and 30 +/- 2 msec in chronic MR), and caused a decrease in the modulus of regional chamber stiffness from 7.7 +/- 1.2 in baseline to 2.4 +/- 0.03 in chronic MR, p < 0.05. MVR caused the resolution of LV dilation (end-diastolic dimension returned to normal [4.8 +/- 0.2 cm]), but three months after MVR, regression of LV hypertrophy was incomplete (LV-to-body weight ratio remained elevated [4.4 +/- 0.5 g/kg]). After MVR, LV early diastolic filling rate (8 +/- 1 cm/sec), the relaxation time constant (31 +/- 2 msec), chamber stiffness (7.1 +/- 1.8), myocardial stiffness (11.2 +/- 3.1), and LV end-diastolic pressure (8 +/- 1 mm Hg) returned to normal. CONCLUSIONS: The enhanced diastolic function seen in chronic MR returned to normal after correction of the chronic volume overload by MVR.
Animals↗
Effects of chronic mitral regurgitation on diastolic function in isolated cardiocytes.
We have previously shown that chronic mitral regurgitation (MR) increases the rate of left ventricular early diastolic filling. These changes in chamber diastolic function were felt to be secondary to alterations in left ventricular loading conditions. Therefore, cellular diastolic function measured in cardiac muscle cells (cardiocytes) isolated from animals with chronic MR (absent alterations in loading conditions) was expected to be normal. However, chronic MR caused a decrease in sarcomere lengthening rate. The purpose of the current study was to define the mechanisms causing this decreased sarcomere lengthening rate in chronic MR cardiocytes and to explain the apparent dichotomy between chamber and cellular diastolic properties. Accordingly, sarcomere motion was measured using laser diffraction techniques in enzymatically isolated cardiocytes from seven control dogs and 11 dogs with chronic MR (produced by closed-chest transection of the mitral chordae). In the MR cardiocytes, there were abnormalities in cellular systolic function (decreased extent and velocity of shortening) and in cellular diastolic function (decreased velocity of sarcomere lengthening). Because studies in papillary muscles have shown that there is a direct relation between abnormal diastolic function (decreased velocity of muscle lengthening) and abnormal systolic function (decreased extent of muscle shortening), it was unclear whether the changes in cellular relaxation rate observed in chronic MR merely reflected a concomitant decrease in the extent of shortening or instead reflected an impairment in intrinsic relaxation properties. To make this distinction, the relation between relaxation velocity (measured as peak sarcomere lengthening rate) and sarcomere shortening extent was examined in MR cardiocytes and compared with that in control cardiocytes. There was a direct relation between sarcomere relaxation velocity and sarcomere shortening extent in both control and MR cardiocytes. Over a wide range of shortening extent, the slopes and y intercepts of this relation were similar in control and MR cardiocytes (slope, 27.7 sec-1 in control cells versus 28.1 sec-1 in MR cells; y intercept, -1.1 microns/sec in control cells versus -1.7 microns/sec in MR cells; p = NS). At any common shortening extent, relaxation velocity was the same in control and MR cardiocytes. To prove that this relation could detect abnormalities in the intrinsic myocardial relaxation process, interventions known to produce primary alterations in the intrinsic myocardial relaxation process were examined: the effects of hypothermia (30 degrees C) and isoproterenol (10(-6) M) on the relaxation velocity-shortening extent relation were studied in normal and MR cardiocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Structural basis for changes in left ventricular function and geometry because of chronic mitral regurgitation and after correction of volume overload.
Left ventricular function and myocyte structure were examined in three groups of dogs: (1) 3 months of mitral regurgitation caused by chordal rupture (n = 7); (2) chronic mitral regurgitation followed by mitral valve replacement and a 3-month recovery period (n = 7), and (3) sham controls (n = 8). The left ventricular end-systolic stiffness constant (Kess) was measured as an index of left ventricular contractile function with stress-strain relationships obtained by cinecatheterization. Isolated myocyte structure and composition were examined with computer-assisted morphometry and nuclear area computed with deoxyribonucleic acid fluorescence. Left ventricular contractile function was significantly depressed with chronic mitral regurgitation compared with control values (Kess, 2.1 +/- 0.1 versus 3.6 +/- 0.2; p < 0.05) and returned to control values with mitral valve replacement (3.8 +/- 0.2). Left ventricular mass significantly increased in both the mitral regurgitation and mitral valve replacement groups compared with control values (121 +/- 10, 120 +/- 5 versus 95 +/- 9 gm, respectively; p < 0.05). Myocyte length increased with mitral regurgitation beyond control values (194 +/- 4 versus 218 +/- 8 microns; p < 0.05) and increased beyond mitral regurgitation values after mitral valve replacement (231 +/- 7 microns; p < 0.05). Myocyte volume with mitral regurgitation increased slightly beyond control values (33.5 +/- 0.7 versus 37.6 +/- 1.3 microns3; p = 0.15) and significantly increased with mitral valve replacement (40.1 +/- 1.2 microns3; p < 0.05). Myocyte myofibril volume significantly declined with mitral regurgitation compared with control values (14.8 +/- 1.5 versus 22.2 +/- 0.7 microns3; p < 0.05) and significantly increased beyond both mitral regurgitation and control values with mitral valve replacement (27.1 +/- 1.1 microns3; p < 0.05). Myocyte nuclear area with mitral regurgitation remained unchanged from control values (1430 +/- 122 versus 1163 +/- 89 microns2) but increased significantly with mitral valve replacement (2209 +/- 250 microns2; p < 0.05). In summary, the left ventricular contractile dysfunction with chronic mitral regurgitation is accompanied by increased myocyte length and reduced myofibril content. In contrast, the left ventricular hypertrophy and improved left ventricular pump function with mitral valve replacement were due to increased myocyte volume and increased contractile protein content.
Animals↗