Survival after Aortic Valve Replacement for Aortic Regurgitation: Prediction from Preoperative Contractility Measurement.

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.

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.

Myocardial Revascularization in New York State: Variations in the PCI-to-CABG Ratio and Their Implications.

BACKGROUND: During the past 2 decades, percutaneous coronary intervention (PCI) has increased dramatically compared with coronary artery bypass grafting (CABG) for patients with coronary artery disease. However, although the evidence available to all practitioners is similar, the relative distribution of PCI and CABG appears to differ among hospitals and regions. METHODS AND RESULTS: We reviewed the published data from the mandatory New York State Department of Health annual cardiac procedure reports issued from 1994 through 2008 to define trends in PCI and CABG utilization in New York and to compare the PCI/CABG ratios in the metropolitan area to the remainder of the State. During this 15-year interval, the procedure volume changes for CABG, for all cardiac surgeries, for non-CABG cardiac surgeries, and for PCI for New York State were -40%, -20%, +17.5%, and +253%, respectively; for the Manhattan programs, the changes were similar as follows: -61%, -23%, +14%, and +284%. The average PCI/CABG ratio in New York State increased from 1.12 in 1994 to 5.14 in 2008; however, in Manhattan, the average PCI/CABG ratio increased from 1.19 to 8.04 (2008 range: 3.78 to 16.2). The 2008 PCI/CABG ratios of the Manhattan programs were higher than the ratios for New York City programs outside Manhattan, in Long Island, in the northern counties contiguous to New York City, and in the rest of New York State; their averages were 5.84, 5.38, 3.31, and 3.24, respectively. In Manhattan, a patient had a 56% greater chance of receiving PCI than CABG as compared with the rest of New York State; in one Manhattan program, the likelihood was 215% higher. CONCLUSIONS: There are substantial regional and statewide differences in the utilization of PCI versus CABG among cardiac centers in New York, possibly related to patient characteristics, physician biases, and hospital culture. Understanding these disparities may facilitate the selection of the most appropriate, effective, and evidence-based revascularization strategy. (J Am Heart Assoc. 2012;1:e001446 doi: 10.1161/JAHA.112.001446.).

Prognosis of a normal positron emission tomography 82Rb myocardial perfusion imaging study in women with no history of coronary disease.

OBJECTIVES: Myocardial perfusion imaging (MPI) with positron emission tomography (PET) has advantages over single-photon emission computerized tomography, particularly for women. This investigation was undertaken to define the prognosis of a normal stress PET MPI study in women. METHODS: The cohort comprised 457 women evaluated for suspected coronary artery disease (CAD) who had normal pharmacologic stress (82)Rb PET MPI. No patient had clinically evident CAD. Kaplan-Meier estimates were used to determine death and initial nonfatal cardiac event rates over 7 years. Log rank tests were used to assess the relationship between baseline cardiac risk and events during follow-up, and to contrast survival in the cohort with age- and gender-matched US census comparators. RESULTS: During follow-up, there were 11 deaths (all nonischemic), 3 nonfatal myocardial infarctions, 3 percutaneous coronary interventions and 1 coronary artery bypass operation. Average risks of death and initial nonfatal cardiac events were 0.72 and 0.47% per year, respectively. Cardiac events were associated with a history of diabetes (p < 0.0003) and a family history of CAD (p < 0.05). CONCLUSION: A normal cardiac PET study is associated with a very low rate of future cardiac events. Women with diabetes and a strong family history of CAD are more likely to sustain events and require close surveillance for the development of coronary disease.

Acceptability and psychometric properties of the Minnesota Living With Heart Failure Questionnaire among patients undergoing heart valve surgery: validation and comparison with SF-36.

BACKGROUND: Health-related quality of life (HQOL) enhancement is a major objective of valvular surgery (VS), but assessments have been limited primarily to generic measures that may not be optimally responsive to intervention. Disease-specific instruments have been used in heart failure (HF), commonly associated with valve disease, but have been neither validated nor routinely applied among patients undergoing VS. METHODS AND RESULTS: We administered the Minnesota Living with Heart Failure (MLHFQ) and SF-36 questionnaires preoperatively (T(0)) to 50 patients undergoing VS and at 1 (T(1)) and 6 months (T(2)) after VS. Performance of MLHFQ was evaluated and compared with SF-36. MLHFQ completion rates were >98% (NS vs. SF-36); Cronbach's alpha was > or = 0.9 (total score, dimensions), supporting internal reliability. Confirmatory factor analysis verified good model fit for physical/emotional domain items (relative chi-squares < 3.0, critical ratios > 2.0, both instruments), supporting structural validity. Spearman coefficients correlating MLHFQ with parallel SF-36 domains were moderate to high (0.6-0.9; P < or = .001: T(0)-T(2)), supporting convergent validity. Baseline HQOL was poorest in patients with HF (P < or = .05 [both instruments]), supporting criterion validity. Responsiveness (proportional HQOL change scores: T(0) vs. T(2)) to VS was greater with MLHFQ vs. SF-36 (P < or = .002). CONCLUSIONS: Among patients undergoing VS, the MLHFQ is highly acceptable and maintains good psychometric properties, comparing favorably with SF-36. These findings suggest its utility for measuring disease-specific HQOL changes after VS.

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.

Prognostic value of exercise tolerance testing in asymptomatic chronic nonischemic mitral regurgitation.

In many heart diseases, exercise tolerance testing (ETT) has useful functional correlates and/or prognostic value. However, its predictive value in mitral regurgitation (MR) is undefined. To determine whether ETT descriptors predict death or indications for mitral valve surgery in patients with MR, we prospectively followed, for 7 +/- 3 end-point-free years, a cohort of 38 patients with chronic severe nonischemic MR who underwent modified Bruce ETT; all lacked surgical indications at study entry. Their baseline exercise descriptors were also compared with those from 46 patients with severe MR who, at entry, already had reached surgical indications. End points during follow-up in the cohort included sudden death (n = 1), heart failure symptoms (n = 2), atrial fibrillation (n = 4), left ventricular (LV) ejection fraction <60% (n = 2), LV systolic dimensions > or =45 mm (n = 12) and >40 mm (n = 11), LV ejection fraction <60% plus LV systolic dimensions > or =45 mm (n = 3), and heart failure plus LV systolic dimensions > or =45 mm plus LV ejection fraction <60% (n = 1). In univariate analysis, exercise duration (p = 0.004), chronotropic response (p = 0.007), percent predicted peak heart rate (p = 0.01), and heart rate recovery (p <0.02) predicted events; in multivariate analysis, only exercise duration was predictive (p <0.02). Average annual event risk was fivefold lower (4.62%) with an exercise duration > or =15 versus <15 minutes (average annual risk 23.48%, p = 0.004). Relative risks in patients with and without exercise-inducible ST-segment depression were comparable (< or =1.3, p = NS) whether defined at entry and/or during follow-up. Exercise duration, but not prevalence of exercise-inducible ST-segment depression, was lower (p <0.001) in patients with surgical indications at entry versus initially end-point-free patients. In conclusion, in asymptomatic patients with chronic severe nonischemic MR and no objective criteria for operation, progression to surgical indications generally is rapid. However, those with excellent exercise tolerance have a relatively benign course. Exercise-inducible ST-segment depression has no prognostic value in this population.

Teaching clinical research methodology to the academic medical community: a fifteen-year retrospective of a comprehensive curriculum.

BACKGROUND: Due to inadequate preparation, many medical professionals are unable to critically evaluate published research articles or properly design, execute and present their own research. AIMS: To increase exposure among physicians, medical students, and allied health professionals to diverse methodological issues involved in performing research. METHOD: A comprehensive course on research methodology was newly designed for physicians and other members of an academic medical community, and has been successfully implemented beginning 1991. The role of the study hypothesis is highlighted; interactive pedagogical techniques are employed to promote audience engagement. Participants complete an annual evaluation to assess course quality and perceived outcomes. Outcomes also are assessed qualitatively by faculty. RESULTS: More than 500 physicians/other professionals have participated. Ratings have been consistently high. Topics deemed most valuable are investigational planning, hypothesis construction and study designs. An enhancement of capacity to define hypotheses and apply methodological concepts in the criticism of scientific papers and development of protocols/manuscripts has been observed. Participants and faculty believe the course improves critical appraisal skills and ability to conduct research. CONCLUSIONS: Our experience shows it is feasible to accomplish these objectives, with a high level of satisfaction, through a didactic program targeted to the general academic community.

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.

Vesnarinone-mediated alterations of gene expression in cardiac fibroblasts from aortic regurgitant hearts.

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.