Impact of Beta-Blockade on Cardiac Events in Patients with Chronic Severe Nonischemic Mitral Regurgitation.

OBJECTIVES: The aim of this study was to examine the impact of beta-blockade on cardiac events among patients with initially asymptomatic chronic severe nonischemic mitral valve regurgitation (MR). METHODS: Data from 52 consecutive patients in our prospective natural history study of isolated chronic severe nonischemic MR were assessed post hoc over 19 years to examine the relation of chronic beta-blockade use to subsequent cardiac events (death or indications for mitral valve surgery, MVS). At entry, all patients were free of surgical indications; 9 received beta-blockers. Cardiac event rate differences were analyzed by Kaplan-Meier log rank comparison. RESULTS: During follow-up, cardiac events included sudden death (1), heart failure (8), atrial fibrillation (6), left ventricular dimensions at systole ≥4.5 cm (11), left ventricular ejection fraction <60% (6), right ventricular ejection fraction <35% (2), and a combination of cardiac events (7). The cardiac event risk was 4-fold higher among patients receiving beta-blockers (average annual risk = 60.6%) versus those not receiving beta-blockers (average annual risk = 15.2%; p = 0.001). These effects remained statistically significant (p = 0.005) when analysis was adjusted for other baseline covariates. CONCLUSIONS: Beta-blockade appears to confer an increased risk of sudden cardiac death or indications for MVS among patients with chronic severe nonischemic MR. Randomized trials are needed to confirm these findings.

Relation of indirect vasodilator use to prognosis in patients with chronic severe mitral regurgitation.

OBJECTIVES: The relation of indirect vasodilator use to cardiac events (CE) is undefined for chronic severe nonischemic mitral regurgitation (MR). The aim of this study was to resolve this knowledge deficiency. METHODS: Data from 52 consecutive patients in our prospective natural history study with isolated chronic severe nonischemic MR were assessed post hoc over 19 years to examine the relation of indirect vasodilator use to subsequent CE (death or indications for valve surgery). At entry, no patient had surgical indications, 14% had hypertension (HTN) and 7 chronically received vasodilators (5 angiotensin-converting enzyme inhibitor, 1 receptor blocker and 1 α-adrenergic blocker). CE differences were assessed by log-rank comparison of Kaplan-Meier curves. RESULTS: During follow-up, CE included sudden death (1 patient), heart failure (7 patients), atrial fibrillation (6 patients), left ventricular (LV) systolic dimension >4.5 cm (12 patients), LV ejection fraction (EF) <60% (7 patients), right ventricular EF <35% (2 patients) and combination CE (7 patients). Overall, vasodilator use did not predict CE (not significant). However, patients without HTN had higher CE rates with vasodilators than without (p = 0.007), while those with HTN and vasodilators had lower CE rates than those without vasodilators (p = 0.04). CONCLUSION: Vasodilator use appears to confer no survival benefit in patients with chronic severe MR. The small number of patients with HTN precludes conclusions about modulation of vasodilator effect by HTN. Randomized trials are needed to conclusively evaluate this association.

Usefulness of preoperative exercise tolerance to predict late survival and symptom persistence after surgery for chronic nonischemic mitral regurgitation.

Exercise duration during exercise treadmill testing (ETT) predicts long-term outcome among asymptomatic patients with mitral regurgitation. However, the prognostic value of preoperative exercise duration in patients who undergo mitral valve surgery is unknown. We examined findings among 45 prospectively followed (average 9.2 ± 4.3 years) patients (aged 54.8 ± 12.0 years, 45% men) with chronic isolated severe MR who underwent ETT before mitral valve surgery to test the hypotheses that exercise duration predicts long-term postoperative survival and persistent symptoms within 2 years after operation. During follow-up, 11 patients died; of these, 8 had persistent symptoms. Among patients who exercised >7 minutes, average annual postoperative all-cause and cardiovascular mortality risks were 0.75% (both endpoints) versus 5.4% and 4.8%, respectively, versus those who exercised ≤7 minutes (p = 0.003 all-cause, p = 0.007 cardiovascular). Exercise duration predicted postoperative deaths (p <.02 all cause, p <.04 cardiovascular) even when analysis was adjusted for preoperative variations in age, gender, medications, history of atrial fibrillation, and peak exercise heart rates. Other ETT, echocardiographic, and clinical variables were not independently associated with these outcomes when exercise duration was considered in the analysis. Preoperative exercise duration also predicted postoperative (New York Heart Association functional class ≥II) symptom persistence (p = 0.012), whereas other ETT, echocardiographic and clinical variables did not (NS, all). In conclusion, among patients who undergo surgery for chronic nonischemic mitral regurgitation, preoperative exercise duration, unlike many commonly used descriptors, is useful for predicting postoperative mortality and symptom persistence. Future research should determine whether interventions to improve exercise tolerance before mitral valve surgery can modify these postoperative outcomes.

Nonischemic mitral regurgitation: prognostic value of nonsustained ventricular tachycardia after mitral valve surgery.

BACKGROUND: Nonsustained ventricular tachycardia (VT), frequent in unoperated severe mitral regurgitation (MR), confers mortality risk [sudden death (SD) and cardiac death (CD)]. The prognostic value of VT after mitral valve surgery (MVS) is unknown; we aimed to define this prognostic value and to assess its modulation by left (LV) and/or right (RV) ventricular ejection fraction (EF) for mortality after MVS. METHODS: In 57 patients (53% females, aged 58 ± 12 years) with severe MR prospectively followed before and after MVS, we performed 24-hour ambulatory electrocardiograms approximately annually. LVEF and RVEF were determined within 1 year after MVS by radionuclide cineangiography. RESULTS: During 9.52 ± 3.49 endpoint-free follow-up years, late postoperative CD occurred in 11 patients (7 SD, 4 heart failures). In univariable analysis, >1 VT episode after MVS predicted SD (p < 0.01) and CD (SD or heart failure; p < 0.04). Subnormal postoperative RVEF predicted CD (p < 0.04). When adjusted for preoperative age, gender, etiology or antiarrhythmics, both postoperative VT and RVEF predicted CD (p ≤ 0.05). When postoperative VT and RVEF were both in the multivariable model, only subnormal RVEF predicted CD (p < 0.04). Among those with normal RVEF, VT >1 episode predicted SD (p = 0.03). CONCLUSION: Postoperative VT and subnormal RVEF predict late postoperative deaths in nonischemic MR. Their assessment may aid patient management.

Fibronectin gene expression in aortic regurgitation: relative roles of mitogen-activated protein kinases.

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.

Differential expression of matrix metalloproteinases and tissue inhibitors and extracellular matrix remodeling in aortic regurgitant hearts.

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.

Cellular response of human cardiac fibroblasts to mechanically simulated aortic regurgitation.

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.

Prognostic impact of systolic hypertension on asymptomatic patients with chronic severe aortic regurgitation and initially normal left ventricular performance at rest.

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.

Left ventricular ejection fraction change with exercise versus ejection fraction at rest in coronary artery disease: implications for using ejection fraction variations in making therapeutic decisions.

Previous studies have differed regarding the prognostic importance of the change (Delta) in left ventricular ejection fraction (LVEF) with exercise among patients with known or suspected coronary artery disease (CAD). Data suggest that these discrepancies may be owing to patient selection, including wide interstudy variations in the range of LVEFrest at study entry; however, the impact of LVEFrest on LVEF exercise response has not been adequately addressed. To test the hypothesis that magnitude and variability in DeltaLVEF are systematically related to LVEFrest, we analyzed data from 2655 patients who underwent rest/exercise radionuclide cineangiography for evaluation of clinically evident CAD, stratified into 5 successive LVEFrest subgroups: <30% (n = 205), 30%-44% (n = 563), 45%-59% (n = 1529), 60%-75% (n = 324), and >75% (n = 34). The standard deviation of DeltaLVEF among patients with LVEFrest <30% was found to be half that among patients in the higher LVEFrest subgroups (P < 0.00001, global). The average magnitude of the rise and fall in LVEF with exercise also varied markedly among LVEFrest subgroups (P < 0.0001, global), being smallest among patients with LVEFrest <30%. These findings may explain differences in predictive accuracy of DeltaLVEF noted among various study populations. Further study is needed to determine whether LVEFrest should be used in selecting exercise-based prognostic descriptors in individual patients.

Myocardial fibrosis in chronic aortic regurgitation: molecular and cellular responses to volume overload.

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.

Localization of (99m)Tc-Labeled ApoB Synthetic Peptide in Arterial Lesions of an Experimental Model of Spontaneous Atherosclerosis.

We have previously shown that after administration of (123)I-SP-4 (a synthetic ApoB peptide fragment) to Watanabe heritable hyperlipidemic (WHHL) rabbits that foci of tracer uptake can be identified by external gamma camera imaging which correspond to regions of the aortas found to contain abundant atherosclerotic lesions at postmortem evaluation. Because (99m)Tc is preferred over (123)I for scintigraphic imaging, we prepared a (99m)Tc-labeled form of the SP-4 peptide, designated (99m)Tc-P199. To assess the feasibility of detecting atherosclerotic lesions using (99m)Tc-P199 and to compare the relative uptake of the (99m)Tc-labeled and radioiodinated peptides by such lesions, an admixture of (99m)Tc-199 and (125)I-SP-4 was administered to 11 WHHL and 2 normal rabbits. These animals were imaged for up to 3 h and were sacrificed 3--4 h after injection. The extent of aortic lesion involvement and radiotracer uptake were quantitatively compared by planimetric analysis of photographs of the endothelial surface, (99m)Tc-P199 ex vivo images and (125)I-SP-4 autoradiograms of the excised aortas. Pairwise correlation coefficients for planimetric analysis were as follows: photographs versus ex vivo images, r = 0.83, p = 0.003; photographs versus autoradiograms, r = 0.87, p = 0.001; ex vivo images versus autoradiograms, r = 0.83, p = 0.003. (99m)Tc-199 in vivo gamma camera images revealed relatively weak focal aortic uptake in 8 of 11 WHHL rabbits manifesting aortic lesions, and focal carotid artery uptake in 4 of 6 WHHL rabbits manifesting carotid lesions. Neither aortic nor carotid foci were visualized in the normal rabbits. We conclude that (99m)Tc-199 localizes specifically in atherosclerotic lesions and may be useful for external imaging of atherosclerosis.