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Objectives: Recent mortality studies showed worse prognosis in patients (ARNS) with severe aortic regurgitation and preserved ejection fraction (EF) not fulfilling the criteria of current guidelines for surgery. The aim of our study was to analyse left ventricular (LV) systolic and diastolic function and mechanical energetics to find haemodynamic explanations for the reduced prognosis of these patients and to seek a new concept for surgery., Methods: Global longitudinal strain (GLS) and echo-based single-beat pressure-volume analyses were performed in patients with ARNS (LV end-diastolic diameter <70 mm, EF >50%, GLS > -19% n = 41), with indication for surgery (ARS; n = 19) and in mild hypertensive controls (C; n = 20). Additionally, end-systolic elastance (LV contractility), stroke work and total energy (pressure-volume area) were calculated., Results: ARNS demonstrated significantly depressed LV contractility versus C: end-systolic elastance (1.58 ± 0.7 vs 2.54 ± 0.8 mmHg/ml; P < 0.001), despite identical EF (EF: 59 ± 6% vs 59 ± 7%). Accordingly, GLS was decreased [-15.7 ± 2.7% (n = 31) vs -21.2 ± 2.4%; P < 0.001], end-diastolic volume (236 ± 90 vs 136 ± 30 ml; P < 0.001) and diastolic operant stiffness were markedly enlarged, as were pressure-volume area and stroke work, indicating waste of energy. The correlation of GLS versus end-systolic elastance was good (r = -0.66; P < 0.001). ARNS and ARS patients demonstrated similar haemodynamic disorders, whereas only GLS was worse in ARS., Conclusions: ARNS patients almost matched the ARS patients in their haemodynamic and energetic deterioration, thereby explaining poor prognosis reported in literature. GLS has been shown to be a reliable surrogate for LV contractility, possibly overestimating contractility due to exhausted preload reserve in aortic regurgitation patients. GLS may outperform conventional echo parameters to predict more precisely the timing of surgery., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Noninvasive measurement of myocardial contractility (end-systolic wall stress-adjusted change in left ventricular ejection fraction from rest to exercise [ΔLVEF - ΔESS]) predicts heart failure, subnormal LVEFrest, and sudden death in asymptomatic patients with chronic severe aortic regurgitation (AR). Here we assess the relation of preoperative ΔLVEF - ΔESS to survival after aortic valve replacement (AVR)., Methods: Patients who underwent AVR for chronic, isolated, pure severe AR (n = 66) were followed for 13.0 ± 6.4 event-free years. Preoperative ΔLVEF - ΔESS (from combined echocardiographic and radionuclide cineangiographic data) enabled cohort stratification into 3 terciles (-1 to -11% [normal or mild] contractility deficit, -12 to -16% [moderate], and ≤-17% [severe], identical with segregation in our earlier study) to relate preoperative contractility to postoperative survival and to age- and gender-matched US census data., Results: Since AVR, 22 patients died (average annual risk [AAR] for all-cause mortality for the entire co hort = 3.15%). Preoperative ΔLVEF - ΔESS predicted postoperative survival (p = 0.009, log rank test). By contractility terciles, all-cause AARs were 1.44, 2.58, and 6.40%. Survival was lower than among US census comparators (p < 0.02), but the "mild" tercile was indistinguishable from census data (p = ns). By multivariable Cox regression, survival prediction by pre-AVR ΔLVEF - ΔESS was independent of, and superior to, prediction by age at surgery, gender, preoperative functional class, LVEFrest, LVEFexercise, change in LVEFrest to exercise, and LV diastolic or systolic dimensions (p ≤ 0.01, pre-AVR ΔLVEF - ΔESS vs. other covariates)., Conclusion: In severe AR, preoperative contractility predicts post-AVR survival and may be prognostically superior to clinical, geometric and performance descriptors, potentially impacting on patient selection for surgery., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Objectives: In aortic regurgitation (AR), fibronectin (FN) expression is upregulated. This study sought to determine signal transduction pathways involved in upregulation of FN expression in AR., Methods: Cardiac fibroblasts (CF) from rabbits with surgically induced AR and matched controls (NL) were cultured and assayed for FN expression and kinase activity with and without inhibitors of kinases JNK, p38 mitogen-activated protein kinase (MAPK) and extracellular response kinase (ERK). NL CF also were subjected to cyclic strain mimicking AR for 24 h in culture with and without inhibitors., Results: AR CF exhibited 2.9-fold greater c-Jun phosphorylation (p < 0.01) and 1.5- to 2-fold greater ATF2 phosphorylation (p < 0.05-0.01) than NL. JNK and p38MAPK inhibition reduced c-Jun and ATF2 phosphorylation to NL; ERK inhibition had no effect. FN mRNA expression was similar in pattern to kinase activities. Cyclic strain in NL CF increased c-Jun phosphorylation 2-fold versus unstrained controls (p < 0.005). This was suppressed by inhibition of JNK but not p38MAPK., Conclusion: FN expression in response to the acute mechanical strain resembling AR is upregulated primarily via JNK. However, in chronic AR both JNK and p38MAPK are involved. These signaling pathways represent potential therapeutic targets for normalizing extracellular matrix (ECM) composition and contractile force transmission, believed to be related to ECM composition/organization, in AR., (Copyright 2009 S. Karger AG, Basel.)

Objectives: Myocardial fibrosis in experimental aortic regurgitation (AR) features abnormal fibronectin with normal collagen content, but the relevant degradative processes have not been assessed., Methods: To elucidate these degradative processes, mRNA (Northern) and protein levels (Western) of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), as well as MMP activity (zymography), were measured in cardiac fibroblasts (CF) from New Zealand white rabbits with experimental AR paired with normals (NL). Collagen and fibronectin were quantified by immunohistochemical staining., Results: In AR CF versus NL CF, MMP-2 and -14 mRNA and protein were increased (both p < 0.005), while TIMPs 1-3 were slightly decreased (p < 0.05-0.005; TIMP-4 undetectable). Gelatinase activity in AR CF was 1.7 times that in NL CF (p < 0.005); fibronectinase activity was unaffected. The Jun N-terminal kinase (JNK) inhibitor SP600125 suppressed MMP-2 protein (0.4-fold, p < 0.05) and mRNA (0.7-fold, p < 0.005) in AR CF; MMP-2 levels in NL CF were unaffected. AR MMP-9 mRNA, protein and activity were low and indistinguishable from NL. In left ventricular tissue, fibronectin was increased 1.9-fold (AR vs. NL, p < 0.05). Total AR collagen was indistinguishable from NL, but the collagen III to collagen I isoform ratio decreased (0.4-fold, p < 0.05)., Conclusions: Collagen is relatively deficient in AR fibrosis, due at least in part to upregulated MMPs and downregulated TIMPs; fibronectinase is unaltered. JNK-dependent regulation may stimulate both MMP-2 and fibronectin expression in AR, providing a potential therapeutic target., (Copyright (c) 2009 S. Karger AG, Basel.)

Myocardial fibrosis has been identified in biopsy specimens from catheterization and valve replacement surgery in patients with severe chronic aortic regurgitation (AR). While characterization of these extracellular matrix (ECM) alterations has been incomplete in humans, fibrosis also has been identified in chronic severe experimentally created AR, in which ECM composition features abnormal fibronectin/glycoprotein production, with normal collagen content. Virtually identical ECM variations have been induced when normal rabbit cardiac fibroblasts (CF) are subjected in culture to cyclic mechanical strain mimicking that found in the left ventricle (LV) in severe AR. To determine whether the changes seen experimentally can be extrapolated to humans, we exposed normal human CF in culture to the mechanical strain employed in the experimental model to simulate severe AR (n=3 replications from 1 patient). CF were isolated from epicardial biopsy distant from diseased coronary arteries in a 38-year-old man with normal LV function and without prior myocardial infarction who was undergoing elective coronary artery bypass grafting. Gelatin Sepharose affinity chromatography (GSAC) and Western analysis were used to compare fibronectin expression in strained versus nonstrained normal human CF in tissue culture; Western analysis was used to compare type I collagen production. In AR-strained CF, fibronectin synthesis nominally increased [av 38% (Western) and 45% (GSAC)] relative to control; type I collagen synthesis was virtually unchanged. These results simulate those found experimentally and suggest that human CF, like rabbit CF, manifest abnormal compositional distribution of ECM proteins in AR.

The influence of systolic hypertension (SH) on the natural history of chronic aortic regurgitation (AR) and the clinical effect of antihypertensive medication on patients who have hypertension and AR are incompletely defined. Therefore, we reviewed the clinical course of 80 unoperated patients who were entered prospectively into an assessment of natural history of AR and its predictors and were asymptomatic with normal left ventricular ejection fraction (LVEF) at rest at study entry; 30 of 80 patients had SH (systolic blood pressure >140 mm Hg); 20 of 80 patients (16 had SH) used antihypertensive drugs for the long term (not mandated by protocol). During an average 7.2-year event-free follow-up, 24 patients developed symptoms alone (n = 14), subnormal LVEF with or without symptoms (n = 8), or died suddenly (n = 2). SH tripled the average annual risk of cardiac events (8.47% vs 2.85%, p = 0.004). The effect of systolic blood pressure was independent of age, gender, diastolic blood pressure, LV diastolic dimension, fractional shortening, and LVEF at rest (p = 0.004 to <0.008). However, positive prognostic interactions existed between systolic blood pressure and pulse pressure (p <0.001), LVEF during exercise (p <0.001), change in LVEF from rest to exercise (p <0.001), and the contractility index (p <0.02). Among patients who had SH, antihypertensive therapy predicted increased event risk (average annual risk 15.46% vs 3.98%, p <0.02) and remained predictive when analysis was adjusted for potentially confounding subgroup variations at study entry (p <0.03, all models). In conclusion, SH portends poor clinical outcome in chronic severe AR. As a group, antihypertensive drugs do not mitigate outcome, although the effect of individual drugs is uncertain and at least some may be deleterious. The theoretically based practice of giving antihypertensive drugs to patients who have AR requires reexamination.

Pathologic fibrosis precedes heart failure (CHF) and death in experimental aortic regurgitation (AR). Vesnarinone, a positively inotropic quinolone derivative, suppresses survival of fibroblasts (CF) from hearts with chronic experimental AR. To explore further the potential effects of vesnarinone on cardiac fibrosis in AR, we tested the hypothesis that vesnarinone suppresses gene expression induced by AR in CF. Differentially expressed genes were isolated by suppression subtractive hybridization (SSH) in CF from hearts of 2 New Zealand White rabbits with surgically induced AR compared with 2 normal rabbits. In cultured AR-CF treated with and without vesnarinone (4 doses, including the dose that had caused maximal survival suppression in cultured AR-CF), drug effect was assessed on expression of genes found to be up-regulated by AR. SSH, reverse Northern analysis, and Northern analysis indicated that at doses several orders of magnitude lower than those used for treatment in CHF vesnarinone significantly down-regulated 2 genes (thrombospondin 1, annexin II) up-regulated by AR. The study confirmed earlier findings of AR-mediated alteration in expression of genes that code for noncollagen extracellular matrix (ECM) proteins. Thus, in CF conditioned by exposure to AR, vesnarinone at relatively low doses suppresses genes coding for 2 noncollagen ECM proteins up-regulated by AR. These pharmacologic effects may underlie potentially therapeutic mitigation of fibrosis by vesnarinone.

Background: Myocardial fibrosis is common in patients with chronic aortic regurgitation (AR). Experimentally, fibrosis with disproportionate noncollagen extracellular matrix (ECM) elements precedes and contributes to heart failure in AR., Methods and Results: We assessed [3H]-glucosamine and [3H]-proline incorporation in ECM, variations in cardiac fibroblast (CF) gene expression, and synthesis of specific ECM proteins in CF cultured from rabbits with surgically induced chronic AR versus controls. To determine whether these variations are primary responses to AR, normal CF were exposed to mechanical strain that mimicked that of AR. Compared with normal CF, AR CF incorporated more glucosamine (1.8:1, P=0.001) into ECM, showed fibronectin gene upregulation (2.0:1, P=0.02), and synthesized more fibronectin (2:1 by Western blot, P<0.06; 1.5:1 by affinity chromatography, P=0.02). Proline incorporation was unchanged by AR (1.1:1, NS); collagen synthesis was unaffected (type I, 0.9:1; type III, 1.0:1, NS). Normal CF exposed to cyclical mechanical strain during culture showed parallel results: glucosamine incorporation increased with strain (2.1:1, P<0.001), proline incorporation was unaffected (1.1:1, NS), fibronectin gene expression (1.6:1, P=0.07) and fibronectin synthesis (Western analysis, 1.3:1, P<0.01; chromatography, 1.9:1, NS) were upregulated., Conclusions: In AR, CF produce abnormal proportions of noncollagen ECM, specifically fibronectin, with relatively little change in collagen synthesis. At least in part, this is a primary response to strain imposed on CF by AR. Further study must relate these findings to the pathogenesis of heart failure in AR.

Extensive primary fibrosis precedes heart failure and death in experimental chronic aortic regurgitation. To seek the molecular basis for this observation, this study analyzed the RNA pool for genes that are up-or downregulated in aortic regurgitation fibroblasts. Differential display reverse transcriptase polymerase chain reaction was used to compare RNA extracted from cardiac fibroblasts isolated from three healthy New Zealand white rabbits and from three with aortic regurgitation. Using two base anchoring oligo d(T) primers (T11VN) together with arbitrary upstream primers, numerous differences in normal versus aortic regurgitation gene expression were apparent on differential display reverse transcriptase polymerase chain reaction. The aortic regurgitation cell cultures showed numerous differentially up-and downregulated genes compared with cell cultures of normal cardiac fibroblasts. The results showed that pathologic fibrosis in chronic experimental aortic regurgitation is associated with abnormal cardiac fibroblast gene expression, which may be pathogenic for the fibrous lesion.

Intercellular conduction in the working myocardium of the mammalian heart is mediated by gap junctions composed of connexin43 or 45. Recently, it has been shown that myocardial connexin expression is malleable and may be altered with disease. To better understand myocardial conduction in left ventricular hypertrophy resulting from volume overload, we used indirect immunofluorescence microscopy to examine cardiac connexin43 expression in 10 New Zealand white rabbits with surgically induced aortic regurgitation (AR) and in 10 age-matched sham-operated controls. Animals were sacrificed at approximately 1 month or > or =2.5 years after operation. All AR animals developed eccentric hypertrophy; none evidenced heart failure. The heart-to-body weight ratios for the 1 month AR and control groups were 2.9+/-0.8 vs 1.8+/-0.2 g/kg (p < or = 0.01) while ratios for the > or =2.5 year AR and control groups were 2.4+/-0.3 vs 1.9+/-0.3 (p < or = 0.05). No significant differences in posterior wall thickness were found among any of the groups. Although the overall pattern of connexin43-like immunoreactivity was similar for all four groups, staining in the I month AR animals tended to be less than that of age-matched controls; staining was increased in the > or =2.5 year AR animals and was greater than control (p < 0.05), in which staining did not change with animal age. This disease duration-related increase differs from the long-term decrease in connexin43 expression associated with other forms of heart disease and suggests that alterations in connexin expression may play a role in the rhythm abnormalities commonly seen in AR.

Vesnarinone, a quinoline derivative with modest positive inotropic action, has been shown in several studies to benefit patients with clinical congestive heart failure. The cellular basis of its clinical benefit is not known, although the drug has several pharmacologic effects demonstrated both in isolated cardiac myocytes and in other noncardiac cell types. To investigate the possibility that the clinical benefit of vesnarinone is based, at least in part, on the inhibition of pathologic myocardial fibrosis, we examined its effects on cultured cardiac fibroblasts isolated from both normal and aortic regurgitant New Zealand White rabbit hearts. As in people, rabbits with moderate-to-severe aortic regurgitation often develop congestive heart failure that, at necropsy, is characterized by exuberant myocardial fibrosis. A dose-response curve was constructed with vesnarinone concentrations ranging from 10(-4 ) to 10(-9 ) mol/L. Cellular survival was decreased by exposure to nanomolar concentrations of drug but not at the higher doses tested. Fibroblasts isolated from normal hearts responded maximally at 10(-7 ) mol/L vesnarinone, whereas fibroblasts from aortic regurgitant hearts responded maximally at 10(-8 ) mol/L. These concentrations of drug are more than an order of magnitude lower than those believed to be associated with clinical benefit from earlier studies. Our results indicate that vesnarinone can suppress cardiac fibroblast proliferation and suggest that this action may be useful in therapies designed to prevent congestive heart failure in aortic regurgitation.

Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic regurgitation (AR), and may be related to the pathophysiology of congestive heart failure (CHF) in this disease. To define the relationship between myocardial histopathologic variations and CHF in chronic AR, we performed gross and microscopic evaluations of postmortem tissue from a rabbit model of chronic AR manifesting left ventricular (LV) responses to AR similar to those in humans. Moderate-to-severe chronic AR (echocardiographic regurgitant fraction = 52 +/- 13%) was induced by closed-chest aortic valve perforation in 11 New Zealand White rabbits; 5 control rabbits were sham operated. Six of the 11 AR rabbits died 1.5 +/- 0.8 years (range 0.6-2.8 years) after AR induction; all 6 had gross and histologic anatomic evidence of CHF at necropsy. The remaining 5 AR rabbits survived until sacrifice at 2.9 +/- 0.1 years of AR; none had pathologic evidence of CHF. Cardiac hypertrophy and the extent of LV fibrosis and myocyte necrosis all were greatest among the 6 AR CHF rabbits. No inflammatory response was apparent in any animal. Moderate-to-severe chronic experimental AR frequently results in CHF which is strongly associated with myocardial fibrosis and necrosis, without evidence of inflammation. These histopathologic variations may be pathophysiologically related to CHF development.

Myocardial fibrosis and abnormal myocardial collagen content are common in many forms of pathological cardiac hypertrophy, including that mediated by pressure overload. Recently, in an experimental animal model of chronic aortic regurgitation (AR), we found a strong relation between myocardial fibrosis and congestive heart failure development. To determine if these fibrotic lesions are composed of collagen, as they are in pressure overload, and to determine if potential preventive therapies should be developed similarly in both diseases, we assessed left ventricular collagen content at three time points after AR induction. Moderate to severe AR was induced in 19 New Zealand White rabbits by inserting a catheter through the carotid artery to perforate the aortic valve leaflets. Animals were killed (1) when they showed echocardiographically discernible systolic dysfunction or (2) if normal cardiac function continued, either early (1 month) or late (>3 years) after operation. Fourteen age-matched, sham-operated controls and seven normal unoperated rabbits also were studied. Collagen concentrations were determined biochemically by hydroxyproline measurement. Fibrosis was measured histologically using Mason's trichrome stain and the fibrous collagen-specific stain, Picro-Sirius Red. Our results show an age-related increase in left ventricular collagen concentration with no specific increase among animals with evidence of fibrosis. We conclude that, unlike pressure overload, volume overload produces fibrotic lesions not composed predominantly of excess collagen and that the therapy needed to prevent fibrosis may be different in these conditions. Further study is needed to define the chemical characteristics of the fibrous lesions and the pathophysiological importance of this finding.

Background: Optimal criteria for valve replacement are unclear in asymptomatic/minimally symptomatic patients with aortic regurgitation (AR) and normal left ventricular (LV) performance at rest. Moreover, previous studies have not assessed the prognostic capacity of load-adjusted LV performance ("contractility") variables, which may be fundamentally related to clinical state. Therefore, 18 years ago, we set out to test prospectively the hypothesis that objective noninvasive measures of LV size and performance and, specifically, of load-adjusted variables, assessed at rest and during exercise (ex), could predict the development of currently accepted indications for operation for AR., Methods and Results: Clinical variables and measures of LV size, performance, and end-systolic wall stress (ESS) were assessed annually in 104 patients by radionuclide cineangiography at rest and maximal ex and by echocardiography at rest; ESS was derived during ex. During an average 7.3-year follow-up among patients who had not been operated on, 39 of 104 patients either died suddenly (n = 4) or developed operable symptoms only (n = 22) or subnormal LV performance with or without symptoms (n = 13) (progression rate=6.2%/y). By multivariate Cox model analysis, change (delta) in LV ejection fraction (EF) from rest to ex, normalized for deltaESS from rest to ex (deltaLVEF-deltaESS index), was the strongest predictor of progression to any end point or to sudden cardiac death alone. Unadjusted deltaLVEF was almost as efficient. Symptom status modified prediction on the basis of the deltaLVEF-deltaESS index. The population tercile at highest risk by deltaLVEF-deltaESS progressed to end points at a rate of 13.3%/y, and the lowest-risk tercile progressed at 1.8%/y., Conclusions: Currently accepted symptom and LV performance indications for valve replacement, as well as sudden cardiac death, can be predicted in asymptomatic/minimally symptomatic patients with AR by load-adjusted deltaLVEF-deltaESS index, which includes data obtained during exercise.

We recently demonstrated dynamic alterations in protein turnover 3 days and 1 month after surgical induction of aortic regurgitation (AR). To characterize protein synthesis and degradation during the long-term plateau phase, we performed [3H]-leucine infusion 2.5 years after induction of AR in 10 New Zealand White rabbits and 12 sham-operated controls. Protein fractional synthesis rates were obtained by analyses of plasma and protein hydrolysates, growth rates from protein concentration and heart weight measurements, and degradation rates by subtraction of growth from synthesis rates. AR (regurgitant fraction 25 +/- 11%) caused a 57% increase in left ventricular (LV) weight in comparison with controls (7.4 +/- 1.7 vs. 4.7 +/- 0.6 g, p < 0.001) and no evidence of heart failure. Although concentrations of total cardiac protein, myosin heavy chain and actin were similar, the enlarged AR hearts had increased amounts of total cardiac protein (1,009 +/- 312 vs. 682 +/- 120 mg/LV, p < 0.05), myosin heavy chain (148 +/- 91 vs. 81 +/- 29 mg/LV, p < 0.05), and actin (73 +/- 42 vs. 44 +/- 16 mg/LV, p < 0.06). Individual protein fractional synthesis and degradation rates were closely balanced. However, myosin fractional synthesis rates were 152% (p < 0.01) greater than those of total cardiac protein in AR animals, while only 52% (p < 0.05) greater in controls (AR vs. controls, p = 0.05). Variations in actin turnover between AR and control animals did not attain statistical significance. Myosin and actin fractional synthesis rates correlated closely in AR rabbits (R = 0.81, p < 0.02), but not among controls (R = 0.41, NS). Thus, selective alterations in myofibrillar protein turnover contribute to the maintenance of increased myofibrillar protein content in the 'compensatory' LV hypertrophy of chronic AR.

We examined the relation of the standard deviation of the 5-minute mean RR intervals over 24 hours (SDANN), a measure of ultra-low frequency heart rate variability (HRV) (<0.0033 Hz), and other measures of HRV to clinical outcome events in 50 asymptomatic or minimally symptomatic patients with chronic severe aortic regurgitation (AR) who underwent ambulatory electrocardiography as part of a prospective study of the natural history of regurgitant valvular diseases. At entry, all patients were in sinus rhythm and had New York Heart Association functional class I or minimal II congestive heart failure, with left ventricular (LV) ejection fraction > or = 45% and LV end-diastolic dimension > or = 5.5 cm in women and > or = 5.9 cm in men. End points were defined as progression to aortic valve replacement (n = 19) or sudden cardiac death (n = 1) during the mean follow-up period of 8.1 +/- 3.8 years. With the median SDANN of 145 ms as a partition value, the average annual risk of end-point events in patients with low SDANN was significantly greater than the event rate in patients with high SDANN (11%/year vs 2%/year, p <0.0003). In multivariate analysis, reduced SDANN was associated with end-point events independent of LV function, LV end-systolic dimension, and symptom status (p = 0.001). We conclude that reduced ultra-low frequency HRV measured as SDANN is strongly related to progression to valve surgery in asymptomatic and minimally symptomatic patients with chronic AR.

Background: Fiber dropout and myocyte necrosis precede heart failure in experimental aortic regurgitation (AR). The current study aimed to determine whether this process can be detected by noninvasive scintigraphic imaging., Methods and Results: 111In-labeled antimyosin antibody Fab fragment (1 to 1.5 mCi) (Myoscint) was administered to each of 34 New Zealand White rabbits: 11 early (3 to 5 weeks) after surgical AR induction; 9 late (98 to 128 weeks) after AR induction; 5 normal and 3 sham-operated age-matched with early AR; and 3 normal and 3 sham-operated age-matched with late AR. Echocardiographic fractional shortening was indistinguishable among control, early AR, and late AR groups. In vivo gamma camera imaging 24 and 48 hours after isotope administration, post-mortem heart activity determination (percentage injected dose per gram), and autoradiography were performed. At 24 and 48 hours, heart-to-lung counts-per-pixel ratios from in vivo images were greater (p < 0.05) in the late AR rabbits than in each of the three other groups. No significant differences were found when early AR and older or younger control rabbits were compared. Heart activity (percentage injected dose per gram) in late AR rabbits trended toward higher values than in age-matched control rabbits (p = 0.057), but in early AR it was indistinguishable from that in the corresponding control (p = 0.413, difference not significant). The autoradiographic endocardial/epicardial activity ratio in late AR rabbits was greater than in control and early AR rabbits (1.27 +/- 0.13 vs 1.06 +/- 0.09 and vs 1.13 +/- 0.10, respectively, p < 0.02)., Conclusions: Whereas isotope uptake in late AR rabbits differed from that in control and early AR rabbits, systolic function was indistinguishable. Thus 111In-labeled antimyosin antibody imaging may permit noninvasive detection of AR-induced myocardial damage before functional deterioration.

The relationship of combined rest and exercise electrocardiographic (ECG) repolarization abnormalities to left ventricular geometry and function was examined in 48 patients with asymptomatic chronic pure aortic regurgitation and no recent use of digitalis. Echocardiographic and radionuclide cineangiographic findings were compared in groups defined by the presence or absence of the "strain" pattern of repolarization abnormality on the resting ECG and also by the presence or absence of standard positive repolarization changes during upright treadmill exercise ( > 0.1 mV additional horizontal or downsloping ST depression). These hierarchic groups demonstrated trends toward progressively abnormal left ventricular dimensions, mass, wall stress, and change in ejection fraction with exercise. Although the presence of the strain pattern on the resting ECG alone was most strongly correlated with underlying functional and geometric abnormalities, an abnormal exercise test response was independently associated with abnormal left ventricular systolic dimension. The large group of patients with no symptoms and normal resting repolarization had only 0% to 4% prevalences of markedly increased systolic dimension (> 55 mm), reduced ejection fraction at rest (< 45%), or reduced ejection fraction during exercise (< 40%), whereas the small group of patients with abnormal resting repolarization and a positive exercise test response had 50% to 83% prevalences of these findings. These data suggest a possible role for rest and exercise ECG in the serial evaluation of patients with aortic regurgitation.

Previously reported experimental models of aortic regurgitation generally have manifested normal systolic performance and have not developed heart failure [Magid et al. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H226-H233, 1992]. To determine whether more severe chronic experimental aortic regurgitation would generate systolic malperformance, heart failure, and emulate the human disease process, 11 New Zealand White rabbits underwent surgical induction of aortic regurgitation and 5 control animals underwent sham operation. Doppler echocardiography was performed serially for up to 3 yr, and pathological studies were performed at necropsy. Left ventricular internal dimension at end diastole increased 80% (P < 0.00002) and left ventricular weight increased 250% (P < 0.0002) in aortic regurgitant rabbits (regurgitant fraction 52 +/- 13%) compared with baseline values. Six of 11 aortic regurgitant animals died with pathological evidence of congestive heart failure at 1.5 +/- 0.8 yr postoperatively; 2 of these developed severe systolic malperformance, manifest as fractional shortenings of 15 and 19% at 1.6 and 1.7 yr, respectively. Five of 11 aortic regurgitant animals survived until killed at 2.9 +/- 0.1 yr. Thus moderate-to-severe chronic aortic regurgitation in rabbits frequently results in heart failure and systolic dysfunction and may usefully model chronic aortic regurgitation and heart failure in humans.

Background: The heart adapts to the volume overload of aortic regurgitation with dilation and hypertrophy. The development of left ventricular hypertrophy at the protein level is a dynamic process resulting from an imbalance between cardiac protein synthesis and degradation. The objective of the present study was to determine in vivo the relative contributions of cardiac protein synthesis and degradation to the progressive hypertrophy that occurs in response to chronic aortic regurgitation and to compare these with responses earlier in the course of this stress., Methods and Results: Continuous intravenous infusions of [3H]-leucine were administered 3 days and 1 month after surgical induction of aortic regurgitation and sham operation in rabbits. Total cardiac protein and myosin heavy chain fractional synthesis rates were obtained by analysis of plasma and protein hydrolysate data using [14C]-dansyl chloride assays. Left ventricular growth rates were determined from serial echocardiographic and postmortem left ventricular weight and protein concentration measurements; protein degradation rates were determined by subtraction of growth rates from synthesis rates., Conclusions: In comparison with sham-operated control rabbits, protein fractional synthesis rates were increased at 3 days but not at 1 month after induction of aortic regurgitation Progressive cardiac hypertrophy occurring at 1 month was caused by a decrease in protein fractional degradation rates. An increase in protein synthesis contributes only to the early phase of hypertrophy caused by acute aortic regurgitation, whereas progressive eccentric hypertrophy in chronic volume overload is due to suppression of protein degradation.

We recently demonstrated that total cardiac protein and myosin heavy chain fractional synthesis rates were not increased during the progressive cardiac hypertrophy that occurred 1 month following induction of aortic regurgitation. The increase in total cardiac protein and myosin heavy chain observed after 1 month of chronic volume overload was caused by a decrease in protein fractional degradation rates. The objective of the present study was to determine in vivo the relative contributions of protein synthesis and degradation of a variety of individual myofibrillar protein constituents, other than myosin heavy chain, to the left ventricular hypertrophic response to chronic aortic regurgitation. Intravenous infusions of [3H]-leucine were administered 3 days and 1 month following surgical induction of aortic regurgitation and sham operation in rabbits, and actin, myosin light chains 1 and 2, alpha-actinin and desmin fractional synthesis rates were obtained by analysis of plasma and protein hydrolysate data using [14C]-dansyl chloride assays. Individual myofibrillar protein growth rates were determined from protein concentration and serial echocardiographic and postmortem left ventricular weight measurements; protein degradation rates were determined by subtraction of growth rates from synthesis rates. Individual myofibrillar protein content increased most rapidly during the 1st week and progressively increased at a slower rate between 1 week and 1 month, in parallel with increases in left ventricular weight. In comparison with sham-operated controls, individual myofibrillar protein fractional synthesis rates were consistently increased at 3 days but not at 1 month. Progressive myocyte hypertrophy occurring at 1 month was caused by a decrease in myofibrillar protein fractional degradation rates. Increased myofibrillar protein synthesis contributed only to the early phase of myocyte hypertrophy while progressive hypertrophy in chronic aortic regurgitation was due to suppression of myofibrillar protein degradation.

Anticardiolipin antibodies (acLa) are associated with a thrombotic tendency (often involving cerebral ischemic events), are frequently present with systemic lupus erythematosus and have been found together with cardiac valve abnormalities. Previous studies evaluated patients characterized by the presence of acLa or lupus, precluding assessment of the frequency of acLa in those with valvular disease. This study aims to establish the prevalence of acLa in patients with valve disease in the absence of lupus and, furthermore, to determine the influence of acLa on the risk of cerebral events in valve disease. Eighty-seven consecutive patients with mitral or aortic regurgitation, or both, prospectively underwent enzyme-linked immunosorbent assay testing for immunoglobulin G (IgG) and M acLa, as did 24 normal subjects. AcLa values greater than or equal to 3 SD above the normal mean were considered "positive." Prior cerebral events were defined retrospectively. Of 87 patients with valvular disease, 26 had positive IgG acLa levels compared with 0 of 24 normal subjects (p less than 0.01). AcLa values did not vary with valve disease etiology. Focal cerebral events had occurred in 8 patients and were embolic or probably embolic in 7, including 7 of 26 IgG acLa-positive and 1 of 60 IgG acLa-negative patients (p less than 0.001). In the absence of lupus, IgG acLa is highly prevalent among patients with aortic or mitral regurgitation, or both; this association may indicate a relatively high risk for cerebral emboli.

To study the time course of left ventricular structural and functional responses to chronic aortic regurgitation, aortic regurgitation was surgically induced in rabbits, and Doppler echocardiography was performed preoperatively and serially postoperatively for up to 2.5 yr. Twenty-five New Zealand White rabbits underwent surgical induction of aortic regurgitation and 13 control animals underwent sham operation. Left ventricular endocardial and epicardial surfaces were digitized from M-mode echocardiograms to measure the rates of change of cavity dimensions and wall thicknesses during diastolic relaxation and systolic contraction. Aortic regurgitant animals developed left ventricular dilatation and eccentric hypertrophy that remained relatively stable throughout the follow-up period. Compared with baseline values, left ventricular mass increased 120% and left ventricular internal dimension at end diastole increased 40%, whereas posterior wall thickness at end diastole and fractional shortening remained relatively stable. Left ventricular diastolic performance was enhanced at 6 mo after operation, a finding associated with increased volume load and heart rate following induction of aortic regurgitation. Diastolic performance was then reduced at 12 mo after operation and demonstrated no further decline throughout the remainder of the follow-up period. In contrast, left ventricular systolic performance was not altered following operation and remained preserved until the final assessment at up to 2.5 yr. Thus alterations in diastolic performance occurred without impairment of systolic performance during long-term follow-up of chronic experimental aortic regurgitation.

Previous studies of left ventricular performance in aortic regurgitation uniformly indicate improvement within the year after aortic valve replacement but differ regarding the likelihood of additional later improvement. To resolve this difference, to more precisely define the pattern of postoperative left ventricular performance variation, and to assess the impact of valve replacement on ejection fraction during exercise, we evaluated radionuclide cineangiograms obtained annually or nearly annually for approximately 5 years in 21 prospectively studied patients who had undergone valve replacement for aortic regurgitation. Ejection fraction rose from less than 8 months before operation to 5-11 (average 7) months after operation and continued to rise for 1 additional year (rest) and 2 additional years (exercise) before reaching a stable plateau until the final study 54-72 (average 63) months postoperatively. Mean ejection fractions at rest were 45% preoperatively, 50% less than 1 year postoperatively (p = 0.12), 54% at year 1-2 (p = 0.01 versus less than 1 year), 56% at year 2-3 (NS versus year 1-2) and year 4-6 (NS versus year 1-2 or 2-3), and during exercise were 39% preoperatively, 49% less than 1 year postoperatively (p less than 0.01), 54% at year 1-2 (p less than 0.01 versus less than 1 year, NS versus year 2-3, p less than 0.05 versus year 4-6), 60% at year 2-3, and 61% at year 4-6 (NS versus year 2-3). Late improvement was found most consistently among patients with relatively depressed performance before operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Left and right ventricular performance characteristics in operative candidates with combined aortic and mitral regurgitation (AR/MR) have not been well defined. Therefore, we determined radionuclide cineangiographic ejection fractions, as well as echocardiographic and hemodynamic parameters, in 8 symptomatic patients undergoing double-valve replacement with pure, severe AR/MR. In order to gain insight into the basis for the poor postoperative survival in patients with this intrinsically biventricular disease, we compared these results with those of 29 symptomatic patients with isolated AR and with 18 symptomatic patients with isolated MR, all also undergoing valve replacement. Before operation, patients with AR/MR had significantly lower left ventricular (LV) ejection fraction than patients with MR (rest, 40 +/- 9% vs 52 +/- 10%, p less than 0.025; exercise, 35 +/- 12% vs 54 +/- 12%, p less than 0.005) and tended to have lower LV ejection fraction than patients with AR alone (rest, 40 +/- 9% vs 45 +/- 12%, difference not significant; exercise, 35 +/- 12% vs 39 +/- 11%, difference not significant); right ventricular (RV) ejection fraction was lower in AR/MR than in AR (p less than 0.01), and tended to be lower than in MR (difference not significant). At average postoperative follow-up of 72 to 76 months (survivors in each group), symptomatic patients with AR/MR had significantly poorer survival than symptomatic patients with isolated MR (p less than 0.05) and were more likely to have persistent symptoms than patients with AR (p less than 0.05). These findings suggest that symptomatic patients with AR/MR have poorer LV and RV performance than similarly symptomatic operative candidates with AR or MR alone.(ABSTRACT TRUNCATED AT 250 WORDS)

In patients with aortic regurgitation,, left ventricular dysfunction at rest, which is associated with a poor long-term prognosis, often develops before severe symptoms. To determine whether evidence of left ventricular dysfunction could be detected before it appeared at rest, 43 patients with severe aortic regurgitation were studied using radionuclide cineangiography during exercise. In 30 normal subjects, left ventricular ejection fraction increased during exercise (57 +/- 1 percent [mean +/- standard error] at rest, 71 +/- 2 percent during exercise, P less than 0.001). In contrast, among 21 symptomatic patients, ejection fraction was normal at rest in 14 patients (average 47 +/- 2 percent) but normal during exercise in only one patient (average 38 +/- 2 percent, P less than 0.001). Ejection fraction was normal at rest in 21 of 22 asymptomatic patients (average 62 +/- 2 percent) but was normal during exercise in only 13 (average 57 +/- 3 percent, P less than 0.001). Thus, exericse-induced left ventricular dysfunction can precede symptoms and dysfunction at rest. Radionuclide assessment of left ventricular function during exercise may prove valuable in sequentially following the state of left ventricular function in patients before the onset of symptoms or of irreversible left ventricular failure.

Although electrocardiographic left ventricular hypertrophy is a recognized marker of disease severity in patients with chronic aortic regurgitation, the quantitative relations of repolarization abnormalities and QRS voltage to measurements of cardiac structure and function have not been established. The presence or absence of the "strain" pattern of repolarization and QRS voltage was compared with echocardiographic and radionuclide cineangiographic findings in 95 adults with sever, pure, chronic aortic regurgitation and no evidence of coronary artery disease. In contrast to 54 patients with normal repolarization, 41 patients with an abnormal repolarization pattern had greater left ventricular end-diastolic and end-systolic dimensions (7.2 +/- 1.1 versus 6.6 +/- 0.8 cm, p less than 0.002 and 5.2 +/- 1.2 versus 4.4 +/- 0.7, p less than 0.001, respectively), greater left ventricular mass (431 +/- 138 versus 303 +/- 89 g, p less than 0.001), higher end-systolic stress (128 +/- 46 versus 95 +/- 27 dynes-cm2 X 10(3), p less than 0.001), lower fractional shortening (28 +/- 8 versus 34 +/- 5%, p less than 0.001) and lower exercise ejection fraction (39 +/- 11 versus 51 +/- 8%, p less than 0.001). Multiple logistic regression analysis revealed that left ventricular mass and end-systolic stress were independently related to the presence of repolarization abnormalities (p less than 0.005). Among the 73 asymptomatic patients, those with normal repolarization had significantly lower prevalences of fractional shortening less than 25% (1 of 45 versus 5 of 27, p less than 0.05), left ventricular systolic dimension greater than 5.5 cm (1 of 45 versus 8 of 27, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Although aortic valve replacement for aortic regurgitation relieves left ventricular volume overload, ventricular geometry does not consistently normalize. To assess the extent, determinants, and functional consequences of reversal of left ventricular dilatation and hypertrophy, 38 patients with severe aortic regurgitation were studied pre- and postoperatively by serial echocardiography and radionuclide cineangiography. Left ventricular end-diastolic dimension normalized in 58% of patients by 9 +/- 6 months postoperatively, at which time 50% of patients had normalized mass; cumulative normalization rose to 66% for end-diastolic dimension and 68% for left ventricular mass during further follow-up. All patients who had normalized end-diastolic dimension also had normal postoperative ejection fractions (mean 61 +/- 8%). In contrast, patients in whom the left ventricle remained dilated had a 42% prevalence of subnormal postoperative left ventricular ejection fraction. Preoperative left ventricular end-systolic dimension less than or equal to 55 mm identified 86% of patients in whom end-diastolic dimension normalized, whereas end-systolic dimension exceeded 55 mm in 81% of those with persistent dilatation; other proposed preoperative predictors of operative outcome correctly identified lower proportions (from 59% to 71%) of patients in whom left ventricular size did or did not normalize. In conclusion, aortic valve replacement resulted in normalized left ventricular chamber size and mass in two thirds of the patients selected for operation by current criteria; favorable geometric outcome is associated with persistence or recovery of normal left ventricular function.

To evaluate the relation of aortic root dilatation to aortic regurgitation, we examined clinical, echocardiographic, and radionuclide cineangiographic findings in 102 patients with severe aortic regurgitation. Aortic root dilatation was the only apparent cause in 31 patients (30%), exceeding in prevalence any valvular cause, and was independently associated only with older age (p less than 0.001). Echocardiography showed dilatation to be either localized to the sinuses of Valsalva or to be generalized. At initial evaluation, patients with generalized dilatation had severer abnormalities of left ventricular size and function than those with localized or no dilatation. Aortic valves were subsequently replaced in more patients with generalized than localized dilatation during 28 +/- 17 month follow-up (9 of 15 patients compared with 2 of 15, p less than 0.03). Thus, idiopathic aortic root dilatation is the commonest definable cause of severe aortic regurgitation; aortic root dilatation is associated independently with age but not blood pressure; and generalized aortic root dilatation is associated with marked ventricular dilatation, hypertrophy, and dysfunction.

Forty-five symptomatic patients with aortic regurgitation underwent graded treadmill exercise testing before operation. Twenty-seven patients (group A) could not complete stage I of the National Institutes of Health exercise protocol because of limiting symptoms (exercise duration less than or equal to 22.5 minutes); 18 patients (group B) completed this stage without limiting symptoms (exercise duration > 22.5 minutes). Patients in group A had higher resting pulmonary capillary wedge pressures (mean 19 vs 13 mm Hg, p < 0.05) and left ventricular (LV) end-diastolic pressures (mean 24 vs 16 mm Hg, p < 0.05) than those in group B, but did not differ with respect to LV systolic dimension or fractional shortening by echocardiography or LV ejection fraction at rest or during exercise by radionuclide cineangiography. Among 32 patients with subnormal preoperative LV fractional shortening on echo, nine of 17 in group A and 0 of 15 in group B have died (p < 0.01); seven of the nine deaths were from late congestive heart failure. Group A patients also had less decrease postoperatively in LV diastolic size by echocardiography (mean decrease 8 vs 23 mm, p < 0.001) and less increase postoperatively in LV ejection fraction during exercise by radionuclide cineangiography (mean increase 11% vs 23%, p 0.05) than group B patients. No group A patient and 60% of group B patients had normal exercise ejection fractions postoperatively (p < 0.01). The differences in postoperative mortality and function were not predicted by the differences in preoperative hemodynamics between the two groups. Thus, exercise capacity is imprecise in assessing preoperative LV function in symptomatic patients with aortic regurgitation, but is useful in predicting long-term survival after operation and reversibility of LV dilatation and systolic dysfunction.

In recent years, exercise testing has become an increasingly important means of evaluating subtle symptomatic changes in patients with aortic and mitral valve disease. Perhaps more significantly, however, when employed with other objective indicators of cardiac function, exercise testing appears to be of value in identifying patients with clinically important deterioration of myocardial function and in assessing the efficacy of various forms of therapy. As investigation of the role of exercise testing in these patients continues, it seems likely that application of exercise testing will prove of value in the rational selection of patients for available therapy.

Fifty consecutive patients undergoing aortic valve replacement for isolated aortic regurgitation were studied prospectively by echocardiography, electrocardiography and cardiac catheterization. Good quality echocardiograms were obtained in 49 of the 50 patients. Left ventricular (LV) dilatation was present in all 49 patients. LV systolic function, as assessed by echocardiographic percent fractional shortening, was normal in many patients but was moderately to severely reduced (less than 25%) in 14 patients (29%). Echocardiographic studies 6 months postoperatively revealed significant reductions in LV end-diastolic dimension (73.8 mm vs 58.7 mm; p less than 0.01), and serial echocardiographic studies early and late after operation revealed that the decrease in LV size had occurred by the time of the early study (8-22 days postoperatively), with little additional change thereafter. Operative deaths occurred in three of the 49 patients (6%). Eight of the 49 patients (16%) died of congestive heart failure (CHF) after hospital discharge at times ranging from 5-43 months after operation. Preoperative echocardiographic measurements of the LV end-systolic dimension and percent fractional shortening were strongly associated (p less than 0.01) with these late CHF deaths. Preoperative LV end-systolic dimension greater than 55 mm and fractional shortening less than 25% identified the high-risk group: nine of 13 patients (69%) in this group died either at operation or subsequently from CHF. In contrast, of 32 patients with LV end-systolic dimension less than 55 mm, only one died at operation and one died late from CHF. Thus, the population at high risk of late death from CHF was identified before operation by echocardiography.

The exercise ECGs of 30 patients with pure aortic regurgitation (AR) were compared with functional and geometric variables measured by echocardiography and radionuclide cineangiography. The 10 patients with positive ECG responses to exercise (greater than or equal to 0.1 mV additional downsloping or horizontal ST segment depression) were similar to the 20 patients with negative tests with respect to mean age, exercise duration, peak work load achieved, symptoms, and resting ECG findings. Patients with positive exercise tests had significantly reduced left ventricular (LV) ejection fractions at rest (44 +/- 4% vs 52 +/- 2%) and during peak exercise (38 +/- 3% vs 48 +/- 2%), lower fractional shortening at rest (27 +/- 1% vs 34 +/- 2%), higher end-systolic wall stress (150 +/- 18 vs 99 +/- 8 dynes/cm2 X 10(3], lower left ventricular relative wall thickness (0.26 +/- 0.01 vs 0.30 +/- 0.01), and greater end-systolic diameter (5.7 +/- 0.3 vs 4.5 +/- 0.2 cm) than patients with negative tests (p less than 0.05 for all comparisons). Among the 18 asymptomatic patients, positive tests were associated with lower resting fractional shortening, lower exercise ejection fraction, higher wall stress, and greater end-systolic diameter. These data demonstrate that a positive exercise ECG in aortic regurgitation identifies patients, even when asymptomatic, who have developed markedly abnormal left ventricular functional and geometric responses to volume load, while a negative exercise ECG identifies a subset of asymptomatic patients who are unlikely to have severe ventricular dysfunction.

To assess the value and predictive limitations of the exercise ST/HR slope, exercise test results were compared in 50 patients with stable angina and in 17 normal subjects with those in two groups known to have a high prevalence of inaccurate electrocardiographic responses to exercise. The last two groups included 51 patients tested within three weeks of acute myocardial infarction and 17 with important aortic regurgitation but no coronary disease. Of the normal subjects, 16 (94%) had ST/HR values less than or equal to 1 X 1 microV/beat/min. Of those with stable angina pectoris, 42 of 46 (91%) patients with coronary artery disease had ST/HR slopes ranging from 1 X 2 to 20 X 0 microV/beat/min, with false negative findings (slopes less than or equal to 1 X 1 microV/beat/min) in only four (9%). In contrast, of those with recent myocardial infarction, 15 of 42 (36%) with coronary disease had false negative slopes, including 12 of 20 (60%) with anterior wall injury. Of those with aortic regurgitation, conversely, 14 of 16 (88%) patients with calculable ST/HR slopes had values greater than 1 X 1 microV/beat/min despite the absence of coronary disease. Despite the accuracy of the test in patients with stable angina, false negative results are common in those after recent myocardial infarction, and false positive results occur often in those with abnormal volume loading due to aortic regurgitation.

Aortic regurgitation was induced by retrograde perforation of an aortic valve cusp under hemodynamic guidance in 12 New Zealand White rabbits. Regurgitant fraction was documented by electromagnetic flow probe and six sham-operated animals served as controls. Two-dimensional, M-mode and Doppler echocardiography was performed pre-operatively and serially post-operatively for 3 to 6 months. Animals with aortic regurgitation developed progressive left ventricular dilatation and eccentric hypertrophy. Left ventricular internal dimension at end-diastole and left ventricular mass were increased from baseline values by 41 and 94% (P less than 0.001), respectively; fractional shortening was stable while end-systolic stress increased 50% (P less than 0.01. Thus, acutely induced aortic regurgitation in rabbits results in a chronic model which may be appropriate for stimulation of the hypertrophic response to aortic regurgitation in humans.

To determine the effect of aortic valve replacement on reversing abnormalities of left ventricular function in patients with aortic regurgitation, radionuclide cineangiography was used to study 16 sympatomatic patients with aortic regurgitation before and 6 months after aortic valve replacement. Before operation, left ventricular ejection fraction was 46 +/- 3 percent at rest (normal mean +/- standard error of the mean 57 +/- 1 percent; P less than 0.001), and decreased to 37 +/- 4 percent during exercise (normal 71 +/- 2 percent; P less than 0.001). after operation, ejection fraction rose to 58 +/- 4 percent at rest, indistinguishable from the normal value, and during exercise was 53 +/- 4 percent, increased (P less than 0.001) from before operation but significantly (P less than 0.001) subnormal. Thus, aortic valve replacement can improve but usually does not normalize left ventricular function during exercise in symptomatic patients with aortic regurgitation.