Retrograde embolism and atherosclerosis development in the human thoracic aorta: are the fluid dynamics explanations valid?

The mechanisms of atherosclerosis development in the thoracic aorta is miscellaneous and still only partially understood. The marked variability of the sites of deposition of atherosclerotic plaques in the aorta could not be clarified based solely on the risk-factors theory of atherosclerosis. The sites of deposition of atherosclerotic plaques are considered to be affected by blood-flow patterns that cause areas of altered shear stress on the aortic wall. Close relations between protruding aortic plaques (PAP), stroke and peripheral emboli were established. The analysis of PAP distribution and motion to characterize atherogenesis in the human thoracic aorta and the pathogeneses of embolic events was performed. We concluded that protruding aortic plaques and markers of relative aortic flow instability (occurrences of vortices) are predominantly noticed in the human arch and in the descending aorta, whereas the ascending aorta showed lesser prevalence of atheromatosis. Reversal and rotational blood-flow in the thoracic aorta most likely exist in all patients with systemic emboli and mobile protruding aortic atheromas. Therefore, retrograde cerebral embolism from distal aortic plaques is conceivable.

Paradoxic decrease in ischemic mitral regurgitation with papillary muscle dysfunction: insights from three-dimensional and contrast echocardiography with strain rate measurement.

BACKGROUND: Ischemic mitral regurgitation (MR) was first ascribed to papillary muscle (PM) contractile dysfunction. Current theories include apical leaflet tethering caused by left ventricular (LV) distortion, but PM dysfunction is still postulated and commonly diagnosed. PM contraction, however, parallels apical tethering, suggesting the hypothesis that PM contractile dysfunction can actually diminish MR due to ischemic distortion of the inferior base alone. METHODS AND RESULTS: We therefore occluded the proximal circumflex circulation in 7 sheep while maintaining PM perfusion, confirmed by contrast echocardiography. By 3D echocardiography, we measured the tethering distance between the ischemic medial PM tip and anterior annulus and LV ejection volume to give MR (by subtracting flowmeter LV outflow). In 6 sheep without initial MR, inferior ischemia alone produced PM tip retraction with restricted leaflet closure and mild-to-moderate MR (regurgitant fraction, 25.2+/-2.8%). Adding PM ischemia consistently decreased MR and tethering distance (5.2+/-0.3 to 1.4+/-0.3 mL; +3.8+/-0.5 mm to -2.2+/-0.7 mm axially relative to baseline; P<0.001) as PM strain rate decreased from +0.78+/-0.07 per second (contraction) to -0.42+/-0.06 per second (elongation, P<0.001) and leaflet tenting decreased. In one sheep, prolapse and MR resolved with inferior ischemia and recurred with PM ischemia. CONCLUSIONS: PM contractile dysfunction can paradoxically decrease MR from inferobasal ischemia by reducing leaflet tethering to improve coaptation. This emphasizes the role of geometric factors in ischemic MR mechanism and potential therapy.

Dobutamine echocardiography in patients with aortic stenosis and left ventricular dysfunction: predicting outcome as a function of management strategy.

STUDY OBJECTIVE: To prospectively address the question whether the assessment of valvular hemodynamics and myocardial function during low-dose dobutamine infusion can guide decision making in patients with aortic stenosis and left ventricular (LV) dysfunction. PATIENTS AND MEASUREMENTS: Twenty-four patients with aortic stenosis and LV dysfunction (mean ejection fraction, 28%; New York Heart Association class, II to IV) were studied by dobutamine echocardiography assessing mean pressure gradient, aortic valve area, and aortic valve resistance. Patients were prospectively divided into severe and nonsevere aortic stenosis groups according to the response of the valve area to the augmentation of systolic flow. The clinical decision was considered to be concordant with the results of dobutamine echocardiography, when patients with severe aortic stenosis and preserved contractile function were referred by a specialist for aortic valve replacement and when patients with nonsevere aortic stenosis were not. Patients were observed for up to 3 years. RESULTS: All eight patients with severe aortic stenosis who were referred for surgery survived and had good cardiovascular outcomes, and six of eight patients who were not initially referred for surgery had poor outcomes, including heart failure and sudden cardiac death. The eight patients with nonsevere aortic stenosis did comparatively well without valve replacement. Cardiac death or pulmonary edema occurred in 4 of 16 patients (25%) when the clinical decision was concordant with the results of the dobutamine echocardiogram and occurred in 6 of 8 patients (75%) when the clinical decision was discordant (p = 0.019 [chi(2) test]). CONCLUSION: Patients with aortic stenosis, LV dysfunction, and relatively low gradients have better outcomes when management decisions are based on the results of dobutamine echocardiograms. Those patients identified as having severe aortic stenosis and preserved contractile reserve by dobutamine echocardiography should undergo surgery, while patients identified as having nonsevere aortic stenosis can be managed conservatively.

A semiautomated objective technique for applying the proximal isovelocity surface area method to quantitate mitral regurgitation: Clinical studies with the digital flow map.

BACKGROUND: Clinical application of the color Doppler proximal isovelocity surface area (PISA) method to quantify mitral regurgitation (MR) has been limited by the often inaccurate assumption that isovelocity surfaces are hemispheric. This study applied an objective method for selecting the region where the hemispheric geometry holds best on the basis of mathematic analysis of results at different distances from the orifice. We aimed to demonstrate this approach can be applied accurately in the clinical setting and can be semiautomated to promote routine use by extracting velocities from the digital Doppler output and then performing all the calculations automatically. METHODS: In 75 patients with isolated MR, centerline velocities (V(r)) at each distance (r) from the orifice in the proximal flow field were extracted digitally. The automated analysis calculated peak MR flow rates as 2pir(2)V(r) and plotted these against their respective velocities. The optimal value for peak flow rate was obtained mathematically at the site where the slope of this curve was minimal (least inaccuracy). This value was combined with continuous wave Doppler data to provide regurgitant stroke volume (RSV) and orifice area (ROA), which were compared with quantitative Doppler in 75 patients and angiography in 42. RESULTS: RSV and ROA by this optimized, semiautomated PISA method correlated and agreed well with values from quantitative Doppler (y = 0.9x + 1.9, r = 0.90, standard error of the estimate [SEE] = 8.1 mL, mean difference = -0.7 +/- 8.5 mL for RSV; y = 0.9x + 0.02, r = 0.90, SEE = 0.048 cm(2), mean difference = -0.005 +/- 0.1 cm(2) for ROA) and correlated well with angiography (rho = 0.90 for both RSV and ROA). CONCLUSIONS: This objective PISA method for quantifying MR is accurate in the clinical setting and has been semiautomated by use of analysis of digital velocity data to provide a rapid and practical technique suitable to facilitate more extensive application in routine practice.

Mechanism of ischemic mitral regurgitation with segmental left ventricular dysfunction: three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation.

OBJECTIVES: This study aimed to separate proposed mechanisms for segmental ischemic mitral regurgitation (MR), including left ventricular (LV) dysfunction versus geometric distortion by LV dilation, using models of acute and chronic segmental ischemic LV dysfunction evaluated by three-dimensional (3D) echocardiography. BACKGROUND: Dysfunction and dilation-both mechanisms with practical therapeutic implications-are difficult to separate in patients. METHODS: In seven dogs with acute left circumflex (LCX) coronary ligation, LV expansion was initially restricted and then permitted to occur. In seven sheep with LCX branch ligation, LV expansion was also initially limited but became prominent with remodeling over eight weeks. Three-dimensional echo reconstruction quantified mitral apparatus geometry and MR volume. RESULTS: In the acute model, despite LV dysfunction with ejection fraction = 23 +/- 8%, MR was initially trace with limited LV dilation, but it became moderate with subsequent prominent dilation. In the chronic model, MR was also initially trace, but it became moderate over eight weeks as the LV dilated and changed shape. In both models, the only independent predictor of MR volume was increased tethering distance from the papillary muscles (PMs) to the anterior annulus, especially medial and posterior shift of the ischemic medial PM, measured by 3D reconstruction (r2 = 0.75 and 0.86, respectively). Mitral regurgitation volume did not correlate with LV ejection fraction or dP/dt. CONCLUSIONS: Segmental ischemic LV contractile dysfunction without dilation, even in the PM territory, fails to produce important MR. The development of MR relates strongly to changes in the 3D geometry of the mitral apparatus, with implications for approaches to restore a more favorable configuration.

Retrograde flow in the thoracic aorta in patients with systemic emboli: a transesophageal echocardiographic evaluation of mobile plaque motion.

STUDY OBJECTIVES: Blood flow in the aorta is complex and incompletely characterized. Mobile aortic plaques (MAPs), moving freely with the pulsatile aortic flow, in fact represent natural tracers that reflect the flow pattern itself. Our aim was to use MAP motion on transesophageal echocardiography (TEE) in order to characterize flow patterns in the atheromatous thoracic aorta of patients with systemic emboli. DESIGN AND PATIENTS: The study group was recruited from 250 patients referred for TEE to evaluate recent embolism. Among them, 22 patients (14 men and 8 women; mean +/- SD age, 66.3 +/- 7.2 years; 16 patients with cerebrovascular and 6 patients with peripheral emboli) with MAPs of > or = 3 mm in length formed the study group. The longest amplitudes of three spatial components of mobile lesion motions were measured: x (antegrade/retrograde [A/R]), y (up/down [U/D], and z (right/left [R/L]). RESULTS: A total of 33 mobile lesions were detected: 3 in the ascending aorta (1 patient), 13 in the arch (10 patients), and 17 in the descending aorta (11 patients). The length of mobile plaque components ranged from 3 to 13 mm; amplitudes of A/R, U/d, R/L, and retrograde flow motions ranged from 3 to 26 mm, from 1 to 16 mm, from 1 to 17 mm, and from 1 to 13 mm, respectively. Systolic rotational motion was clockwise in six patients (27%), counterclockwise in five patients (23%), incomplete (semicircle) in six patients (27%), and alternate clockwise/counterclockwise in five patients (23%). Diastolic rotational motion was clockwise in 5 patients (23%), counterclockwise in 6 patients (27%), and incomplete (semicircle) in 11 patients (50%). There were 18 multiple MAPs in seven patients: in all these cases, simultaneous rotations of MAP in different directions (as a marker for the presence of multiple vortices) were found. In nine patients with cerebral embolism, MAPs on the distal part of aortic arch solely were found; in five of them, all alternative potential sources of stroke were excluded. Therefore, retrograde cerebral embolism from distal aortic plaques in these patients is highly probable. CONCLUSIONS: Retrograde and rotational blood flow in the thoracic aorta probably exists in all patients with systemic emboli and mobile protruding aortic atheromas. Therefore, retrograde cerebral embolism from distal aortic plaques is theoretically possible.

Impact of atrioventricular compliance on pulmonary artery pressure in mitral stenosis: an exercise echocardiographic study.

BACKGROUND: The decay of the pressure gradient across a stenotic mitral valve is determined by the size of the orifice and net AV compliance (C(n)). We have observed a group of symptomatic patients, usually in sinus rhythm, characterized by pulmonary hypertension (particularly during exercise) despite a relatively large mitral valve area by pressure half-time. We speculated that this discrepancy was due to low atrial compliance causing both pulmonary hypertension and a steep decay of the transmitral pressure gradient despite significant stenosis. We therefore tested the hypothesis that C(n) is an important physiological determinant of pulmonary artery pressure at rest and during exercise in mitral stenosis. METHODS AND RESULTS: Twenty patients with mitral stenosis were examined by Doppler echocardiography. C(n), calculated from the ratio of effective mitral valve area (continuity equation) and the E-wave downslope, ranged from 1.7 to 8.1 mL/mm Hg. Systolic pulmonary artery pressure (PAP) increased from 43+/-12 mm Hg at rest to 71+/-23 mm Hg (range, 40 to 110 mm Hg) during exercise. There was a particularly close correlation between C(n) and exercise PAP (r=-0.85). Patients with a low compliance were more symptomatic (P<0.025). Catheter- and Doppler-derived values for C(n), determined in 10 cases, correlated well (r=0.79). CONCLUSIONS: C(n), which can be noninvasively assessed, is an important physiological determinant of PAP in mitral stenosis. Patients with low C(n) represent an important clinical entity, with symptoms corresponding to severe increases in PAP during stress echocardiography.

Prognostic significance of mild mitral regurgitation by color Doppler echocardiography in acute myocardial infarction.

Mitral regurgitation (MR) complicating acute myocardial infarction (AMI) is associated with increased mortality. The prognostic significance of only mild MR detected by echocardiography in patients with AMI is unknown. This study assessed the long-term risk associated with mild MR detected by color Doppler echocardiography within the first 48 hours of admission in 417 consecutive patients with AMI. No MR was detected in 271 patients (65%), mild MR was seen in 121 patients (29%), and moderate or severe MR was noted in 25 patients (6%). One-year mortality rates were 4.8%, 12.4%, and 24%, respectively (p<0.001). Multivariate analysis revealed that mild MR was independently associated with increased 1-year mortality (p<0.05) after adjustment for age, gender, previous myocardial infarction, diabetes mellitus, systemic hypertension, Killip grade > or =2 on admission, and left ventricular ejection fraction < or =40%. The hazard ratio for 1-year mortality was 2.31 (95% confidence interval 1.03 to 5.20) for mild MR and 2.85 (95% confidence interval 0.95 to 8.51) for moderate or severe MR. Thus, mild MR detected by color Doppler echocardiography within the first 2 days of admission in patients with AMI is a significant independent risk predictor for 1-year all-cause mortality.

Fluid dynamics and atherosclerosis development in the human thoracic aorta: a transesophageal echocardiographic evaluation of protruding aortic plaque distribution and motion.

The pathogeneses of atherosclerosis in the thoracic aorta is heterogeneous and still incompletely elucidated. Protruding aortic plaques (PAP), reliable markers of atherosclerosis development and extension, could be easily identified by transesophageal echocardiography (TEE). A close relation between atherosclerosis development in the thoracic aorta, stroke and peripheral emboli were established. The purpose of this study was to use PAP distribution and motion on TEE to characterize atherogenesis in the human thoracic aorta. Out of 569 consecutive patients (age range 18-83 years), 108 were referred for TEE to evaluate recent embolism (Group I). The remaining 461 patients were referred for TEE for reasons unrelated to embolism (Group II). The plaque thickness was measured perpendicularly to the aortic wall. In the subgroup of patients with multiple mobile lesions, multiple vortices were suggested to be present when simultaneous rotations in different directions were found. The presence of a fixed PAP was associated with a statistically significant, albeit moderate, increase in the risk for embolism (adjusted odds ratio 4.1). The presence of mobile lesions was linked to an abrupt augmentation in this risk (adjusted odds ratio 30.1). Among the 35 patients in Group I there were 69 PAP: 8 (12%) in the ascending, 28 (41%) in the arch and 33 (48%) in the descending aorta. A total of 34 mobile lesions was detected: 1 (one patient) in the ascending aorta, 15 (10 patients) in the arch and 18 (11 patients) in the descending aorta. There was no significant difference between the arch and the descending aorta regarding the frequency of the plaques in these regions, whereas the ascending aorta presented the lowest prevalence for atheromatosis. Diastolic retrograde and rotational flows were observed in all patients. There were 16 multiple mobile PAP in 6 patients: in all these cases simultaneous rotations of mobile aortic plaques (MAP) in different directions (highly suggestive for the presence of multiple vortices and significant flow instability) were found in the arch and the descending but not the ascending aorta. Protruding aortic plaques and signs of relative aortic flow instability (presence of vortices) are mainly observed in the human arch and in the descending aorta, whereas the ascending aorta presented the lowest prevalence for atheromatosis. This issue may have significant implications in the study of atherosclerosis development in the human thoracic aorta and the pathogeneses of embolic events.

Noninvasive assessment of left ventricular end-diastolic pressure by the response of the transmitral a-wave velocity to a standardized Valsalva maneuver.

Impaired relaxation is frequently masked by elevated filling pressures, resulting in a pseudonormal flow pattern (E/A >1.0). Because the E/A wave ratio increases as filling pressures rise, it is generally assumed that patients with an E/A ratio of <1.0 (impaired relaxation pattern) have relatively low filling pressures. Nevertheless, patients with an E/A ratio of <1.0 can have as profoundly elevated filling pressures as patients with a pseudonormal or restrictive filling pattern. Because left ventricular (LV) pressure during end-diastole essentially determines atrial afterload, the response of the A-wave velocity to a reduction of atrial afterload by a standardized Valsalva maneuver should allow estimation of LV end-diastolic pressure (LVEDP) regardless of the baseline Doppler flow pattern. This was tested in 20 consecutive patients who were studied by pulse-wave Doppler echocardiography during cardiac catheterization. There was a close correlation between LVEDP and the change in A-wave velocity during the Valsalva maneuver (r = 0.85, SEE 6.7 mm Hg) regardless of the baseline E/A ratio. In patients with a LVEDP of <15 mm Hg the A wave decreased by 21 +/- 15 cm/s. In patients with a LVEDP of >25 mm Hg the A wave increased by 18 +/- 13 cm/s. The change in the E/A ratio during Valsalva correlated fairly with LVEDP (r = -0.72, SEE 8.8 mm Hg), the baseline E/A ratio correlated poorly, and scatter was substantial (r = 0.46, SEE 11.2 mm Hg). Just as elevated filling pressures can mask impaired relaxation, the impaired relaxation pattern can mask the presence of elevated filling pressures. This can be revealed by testing the response of the A wave to the Valsalva maneuver, allowing estimation of LVEDP independent of the baseline E/A ratio.

Assessment of pseudohypertrophy as a measure of left-ventricular compression in patients with cardiac tamponade.

BACKGROUND: Left-ventricular pseudohypertrophy reflecting left-ventricular compression was reported in a selected group of patients with cardiac tamponade. HYPOTHESIS: Criteria for the presence of pseudohypertrophy can be established to guide its use as a sign of left-ventricular compression in patients with cardiac tamponade. METHODS: Left-ventricular wall thickness, diameters, relative diastolic wall thickness (%) = (posterior wall thickness/end diastolic radius) x 100 and estimated left-ventricular mass were measured in patients with small, moderate and large pericardial effusion, in patients with cardiac tamponade before and after pericardiocentesis (16 patients in each group) and in 30 control subjects with normal echocardiograms. RESULTS: Left-ventricular posterior wall thickness was increased (12 +/- 2 vs. 9 +/- 1 mm, p < 0.001), left-ventricular end-diastolic diameter was reduced (3.9 +/- 0.5 vs. 4.6 +/- 0.3 cm, p < 0.001) and relative left-ventricular diastolic wall thickness was increased (61 +/- 13 vs. 41 +/- 4.5%, p < 0.001) only in patients with cardiac tamponade compared to controls, but not in patients with small, moderate and large effusions, respectively (relative wall thickness: 42 +/- 5, 41 +/- 7 and 44 +/- 7%, p = NS). Mean values of the estimated left-ventricular mass were similar in all groups. Following pericardiocentesis all parameters were normal. CONCLUSIONS: Despite normal left-ventricular mass, relative left-ventricular diastolic wall thickness is elevated in patients with cardiac tamponade. In contrast it is normal in patients with various degrees of pericardial effusion supporting its use as a quantitative measure of left-ventricular compression in patients with suspected cardiac tamponade.

Mechanism of dynamic regurgitant orifice area variation in functional mitral regurgitation: physiologic insights from the proximal flow convergence technique.

OBJECTIVES: We used the Doppler proximal flow convergence technique as a physiologic tool to explore the effects of the time courses of mitral annular area and transmitral pressure on dynamic changes in regurgitant orifice area. BACKGROUND: In functional mitral regurgitation (MR), regurgitant flow rate and orifice area display a unique pattern, with peaks in early and late systole and a midsystolic decrease. Phasic changes in both mitral annular area and the transmitral pressure acting to close the leaflets, which equals left ventricular-left atrial pressure, have been proposed to explain this dynamic pattern. METHODS: In 30 patients with functional MR, regurgitant orifice area was obtained as flow (from M-mode proximal flow convergence traces) divided by orifice velocity (v) from the continuous wave Doppler trace of MR, transmitral pressure as 4v(2), and mitral annular area from two apical diameters. RESULTS: All patients had midsystolic decreases in regurgitant orifice area that mirrored increases in transmitral pressure, while mitral annular area changed more gradually. By stepwise multiple regression analysis, both mitral annular area and transmitral pressure significantly affected regurgitant orifice area; however, transmitral pressure made a stronger contribution (r2 = 0.441) than mitral annular area (added r2 = 0.008). Similarly, the rate of change of regurgitant orifice area more strongly related to that of transmitral pressure (r2 = 0.638) than to that of mitral annular area (added r2 = 0.003). A similar regurgitant orifice area time course was observed in four patients with fixed mitral annuli due to Carpentier ring insertion. CONCLUSIONS: In summary, the time course and rate of change of regurgitant orifice area in patients with functional MR are predominantly determined by dynamic changes in the transmitral pressure acting to close the valve. Thus, although mitral annular area helps determine the potential for MR, transmitral pressure appears important in driving the leaflets toward closure, and would be of value to consider in interventions aimed at reducing the severity of MR.

Mechanism of mitral regurgitation in hypertrophic cardiomyopathy: mismatch of posterior to anterior leaflet length and mobility.

BACKGROUND: In hypertrophic cardiomyopathy, a spectrum of mitral leaflet abnormalities has been related to the mechanism of mitral systolic anterior motion (SAM), which causes both subaortic obstruction and mitral regurgitation. In the individual patient, SAM and regurgitation vary in parallel; clinically, however, great interindividual differences in mitral regurgitation can occur for comparable degrees of SAM. We hypothesized that these differences relate to variations in posterior leaflet length and mobility, restricting its ability to follow the anterior leaflet (participate in SAM) and coapt effectively. METHODS AND RESULTS: Different mitral geometries produced surgically in porcine valves were studied in vitro. Comparable degrees of SAM resulted in more severe mitral regurgitation for geometries characterized by limited posterior leaflet excursion. Mitral geometry was also analyzed in 23 patients with hypertrophic cardiomyopathy by intraoperative transesophageal echocardiography. All had typical anterior leaflet SAM with significant outflow tract gradients but considerably more variable mitral regurgitation; therefore, regurgitation did not correlate with obstruction. In contrast, mitral regurgitation correlated inversely with the length over which the leaflets coapted (r= -0.89), the most severe regurgitation occurring with a visible gap. Regurgitation increased with increasing mismatch of anterior to posterior leaflet length (r=0.77) and decreasing posterior leaflet mobility (r= -0.79). CONCLUSIONS: SAM produces greater mitral regurgitation if the posterior leaflet is limited in its ability to move anteriorly, participate in SAM, and coapt effectively. This can explain interindividual differences in regurgitation for comparable degrees of SAM. Thus, the spectrum of leaflet length and mobility that affects subaortic obstruction also influences mitral regurgitation in patients with SAM.

Disrupted mobile aortic plaques are a major risk factor for systemic embolism in the elderly.

Protruding aortic plaques--especially those with mobile properties--on transesophageal echocardiography (TEE) are a potential source of stroke and systemic embolism in the elderly. Whether the various morphologies of atheromas with mobile components represent potential differences in the risk for embolic events has not been thoroughly elucidated. The goal of the present study was to determine the association between embolic events and the various types of mobile lesions in the thoracic aorta. Our population consisted of 569 consecutive patients (age 18-83 years) referred for TEE over 27 months; 108 (19%) of them were referred to evaluate recent embolism (cerebral in 97 and peripheral or both in 11; group I) and the remaining 461 were admitted for reasons unrelated to embolism (group II). In group I, 35 patients (32%) exhibited protruding plaques; those were fixed in 10 (9%) and with a mobile component in 25 (23%). In group II, plaques were found in only 13 patients (3%); fixed in 9 (2%) and mobile in 4 (1 %). Twenty-four patients with mobile lesions in group I were > 50 years old, and 21 of them (88%) were > 60 years old. While the presence of fixed plaques was associated with a moderate increase in the risk for systemic embolism (adjusted odds ratio 4.1; 95% confidence interval 1.3-56.4), mobile lesions were linked to a striking augmentation of this risk (odds ratio 30.1; 95% confidence interval 7.8-132.6). The majority of mobile lesions (76%) in group I represented disrupted atheromas with characteristic ulcerations or echolucency within the plaque suggestive of intraatheroma hemorrhage, whereas these TEE features were not observed in 89% of the mobile lesions in group II (p = 0.0003). We conclude that among the various types of mobile aortic lesions, the disrupted protruding plaques are a major risk factor for stroke and embolic events in the elderly.

Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies.

BACKGROUND: Functional mitral regurgitation in patients with ischemic or dilated ventricles has been related to competing factors: altered tension on the leaflets due to displacement of their papillary muscle and annular attachments, which restricts leaflet closure, versus global ventricular dysfunction with reduced transmitral pressure to close the leaflets. In vivo, however, geometric changes accompany dysfunction, making it difficult to study these factors independently. Functional mitral regurgitation also paradoxically decreases in midsystole, despite peak transmitral driving pressure, suggesting a change in the force balance acting to create a regurgitant orifice, with rising transmitral pressure counteracting forces that restrict leaflet closure. In vivo, this mechanism cannot be tested independently of annular contraction that could also reduce midsystolic regurgitation. METHODS AND RESULTS: An in vitro model was developed that allows independent variation of papillary muscle position, annular size, and transmitral pressure, with direct regurgitant flow rate measurement, to test the hypothesis that functional mitral regurgitation reflects an altered balance of forces acting on the leaflets. Hemodynamic and echocardiographic measurements of excised porcine valves were made under physiological pressures and flows. Apical and posterolateral papillary muscle displacement caused decreased leaflet mobility and apical leaflet tethering or tenting with regurgitation, as seen clinically. It reproduced the clinically observed midsystolic decrease in regurgitant flow and orifice area as transmitral pressure increased. Tethering delayed valve closure, increased the early systolic regurgitant volume before complete coaptation, and decreased the duration of coaptation. Annular dilatation increased regurgitation for any papillary muscle position, creating clinically important regurgitation; conversely, increased transmitral pressure decreased regurgitant orifice area for any geometric configuration. CONCLUSIONS: The clinically observed tented-leaflet configuration and dynamic regurgitant orifice area variation can be reproduced in vitro by altering the three-dimensional relationship of the annular and papillary muscle attachments of the valve so as to increase leaflet tension. Increased transmitral pressure acting to close the leaflets decreases the regurgitant orifice area. These results are consistent with a mechanism in which an altered balance of tethering versus coapting forces acting on the leaflets creates the regurgitant orifice.

Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry.

BACKGROUND: Recent advances in three-dimensional (3D) echocardiography allow us to address uniquely 3D scientific questions, such as the mechanism of functional mitral regurgitation (MR) in patients with left ventricular (LV) dysfunction and its relation to the 3D geometry of mitral leaflet attachments. Competing hypotheses include global LV dysfunction with inadequate leaflet closing force versus geometric distortion of the mitral apparatus by LV dilatation, which increases leaflet tethering and restricts closure. Because geometric changes generally accompany dysfunction, these possibilities have been difficult to separate. METHODS AND RESULTS: We created a model of global LV dysfunction by esmolol and phenylephrine infusion in six dogs. initially with LV expansion limited by increasing pericardial restraint and then with the pericardium opened. The mid-systolic 3D relations of the papillary muscle (PM) tips and mitral valve were reconstructed. Despite severe LV dysfunction (ejection fraction, 18+/-6%), only trace MR developed when pericardial restraint limited LV dilatation; with the pericardium opened, moderate MR accompanied LV dilatation (end-systolic volume, 44+/-5 mL versus 12+/-5 mL control, P<.001). Mitral regurgitant volume and orifice area did not correlate with LV ejection fraction and dP/dt (global function) but did correlate with changes in the tethering distance from the PMs to the anterior annulus derived from the 3D reconstructions, especially PM shifts in the posterior and mediolateral directions, as well as with annular area (P<.0005). By multiple regression, only changes in the PM-to-annulus distance independently predicted MR volume and orifice area (R2=.82 to .85, P=2x10(-7) to 6x10(-8)). CONCLUSIONS: LV dysfunction without dilatation fails to produce important MR. Functional MR relates strongly to changes in the 3D geometry of the mitral valve attachments at the PM and annular levels, with practical implications for approaches that would restore a more favorable configuration.

Patients with valvular heart disease presenting with sustained ventricular tachyarrhythmias or syncope: results of programmed ventricular stimulation and long-term follow-up.

BACKGROUND: Programmed ventricular stimulation is commonly used to guide therapy in post-myocardial infarction patients with sustained monomorphic ventricular tachycardia (VT) or ventricular fibrillation (VF). In patients with valvular heart disease presenting with spontaneous VT, VF, or syncope, the usefulness of this technique is still unclear. The aim of the study was to analyze whether programmed ventricular stimulation was helpful in guiding therapy and determining prognosis in 97 patients with valvular heart disease presenting with VT (60%), VF (18%), or syncope (22%). METHODS AND RESULTS: Patients were classified as having either predominant ventricular pressure or volume overload or no significant pressure or volume overload. Overall, sustained VT or VF was inducible in 38 (39%) and 19 (20%) patients, respectively. Forty-six (47%) patients were discharged on antiarrhythmic drugs, 29 (30%) received an implantable cardioverter-defibrillator, and 22 (23%) remained without therapy. With serial drug testing, inducibility was completely or partially suppressed in 18 (19%) and 9 (9%) patients, respectively. During a mean follow-up of 51 months (n=97), 17 patients (18%) died (sudden death, n=7; heart failure, n=4; noncardiac causes, n=6). One-, 2- and 3-year event-free survival for sudden death, sustained VT, or VF was 77%, 68%, and 61%, respectively. Only inducibility of VT during baseline study (P<.0003) and left ventricular volume overload (P<.008) were significant predictors of arrhythmic events. Recurrence of arrhythmic events occurred in 56% and 56% of patients with complete or partial suppression of inducibility during serial drug testing as well as in 10 of 19 (53%) patients without a change in inducibility. CONCLUSIONS: Although programmed ventricular stimulation seems to predict adverse outcome, serial drug testing is unreliable in guiding therapy. The type of workload imposed on the ventricles influences outcome, being worse in patients with left ventricular volume overload. Therefore, implantation of a cardioverter-defibrillator should be considered early for the management of these patients.

Stress echocardiography beyond coronary artery disease.

Doppler echocardiography has become the major diagnostic tool of evaluation of valvular heart disease and the cardiomyopathies because of its ability to provide valuable haemodynamic information accurately and non-invasively. It is therefore ideally suited for haemodynamic stress testing in these patients. In aortic stenosis, dobutamine echocardiography can distinguish severe from non-severe stenosis in patients with depressed left ventricular function, low transvalvular gradients, and a relatively small (flow-related) valve area at baseline. Patients with non-severe aortic stenosis increase cardiac output and valve area with dobutamine infusion while the transvalvular gradient does not change significantly. In severe aortic stenosis, the pressure gradient increases significantly with stroke volume, but valve area does not. In patients who fail to increase stroke volume (absent contractile reserve) and therefore do not show a change in haemodynamics, the severity of the lesion is 'indeterminate'; these patients are characterized by a very poor prognosis. In mitral stenosis, patients can be identified who increase valve area during exercise, which is the fundamental mechanism by which stroke volume can be increased in mitral stenosis. The increase in pulmonary artery pressure during exercise (assessed from tricuspid regurgitant signal) can be dramatically different in patients with comparable resting haemodynamics; therefore exercise echocardiography provides information which cannot be obtained from resting measurements alone and can help to guide medical and surgical therapy. Whether stress echocardiography may be similarly helpful in patients with regurgitant lesions is still a subject of investigation. Exercise Doppler echocardiographic studies following aortic valve replacement (small valves) can identify impairment of systolic and diastolic function indicative of 'valve prosthesis-patient mismatch'. In hypertrophic cardiomyopathy the dynamics of outflow obstruction can be assessed following exercise or pharmacological intervention. In dilative cardiomyopathy, contractile reserve can be assessed by dobutamine echocardiography which may help in evaluating prognosis, guiding heart failure therapy, and monitoring therapy with cardiotoxic chemotherapeutic agents.