Phyllis G. Supino

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. Method 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.

Teaching evidence-based medicine to medical students.

Given the proliferation of published studies and clinical updates, knowing how to use the literature effectively and efficiently is a necessary skill. Many medical schools in the United States are requiring courses in evidence-based medicine (EBM) in an effort to teach medical students how to distinguish high- from low-quality studies, how to interpret results from systematic reviews, and how to recognize flaws in study design or in methodology. The Department of Public Health of the Weill Medical College of Cornell University, in collaboration with the Information Service of the Library, initiated a required EBM course in the first year of medical school. This four-week comprehensive course in the concepts and techniques of EBM focused on methods, study design and statistical analysis in assigned articles as well as on instruction in database-searching techniques. This report reviews the process of implementing such a course and factors needed to ensure the realization of its objectives.

Preoperative Predictors of Late Postoperative Outcome among Patients with Nonischemic Mitral Regurgitation with 'High Risk' Descriptors and Comparison with Unoperated Patients

Among patients with chronic nonischemic mitral regurgitation (MR), high short-term mortality risk can be identified by left (LV) and/or right ventricular (RV) ejection fraction (EF) criteria (LVEF ≤45% and/or RVEF ≤30%). Mitral valve replacement or repair (MVR) significantly improves outcome in this subgroup, but predictors of late postoperative survival are not known, and the benefit of MVR has not been defined in patients matched for severity of LV and RV dysfunction. Therefore, prospective assessment of 14 consecutive high risk MR patients was performed before MVR and during 9 years (average) postoperatively to define echocardiographic and radionuclide angiographic predictors of survival; survival also was evaluated in a contemporaneous series of 9 high risk unoperated MR patients, and in subgroups of operated and unoperated patients matched for EF. Of 14 MVR patients, 4 died (3 cardiac: 1 sudden, 2 congestive heart failure). Only preoperative RVEF ≤20% significantly predicted postoperative deaths (rest p = 0.032; exercise p = 0.05). Of 9 unoperated patients, 8 died. Mortality risk of unoperated patients remained higher than that of MVR patients when groups were matched for preoperative LVEF (p = 0.0001). Among patients with RVEF >20%, MVR significantly improved survival versus medical treatment (rest: p < 0.0001, exercise: p = 0.0003). In high risk MR patients, MVR improves survival; preoperative RV performance can define subgroups with different long-term postoperative survival.

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); Cronbachs 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.

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.

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 82Rb 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.

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.)

Prognostication in 3-Vessel Coronary Artery Disease Based on Left Ventricular Ejection Fraction During Exercise Influence of Coronary Artery Bypass Grafting

BACKGROUND Previous data indicate that left ventricular ejection fraction (LVEF) provides prognostic information among patients with coronary artery disease (CAD), but the value of such testing specifically for defining benefits of coronary artery bypass grafting (CABG) may relate to severity of exercise-inducible ischemia measured noninvasively before surgery. METHODS AND RESULTS To determine the independent prognostic importance of preoperative ischemia severity for predicting outcomes of CABG among patients with extensive CAD, we monitored 167 stable patients with angiographically documented 3-vessel CAD (average follow-up of 9 years in event-free patients) who previously had undergone rest and exercise radionuclide cineangiography. Their course was correlated with data obtained during initial radionuclide testing, coronary arteriography, and clinical evaluation at study entry. Fifty-two patients received medical treatment only, and 115 underwent CABG (44 early [</=1 month after initial study]). Multivariate Cox model analysis indicated that change (Delta) in LVEF from rest to exercise during radionuclide study was the strongest independent predictor of major cardiac events (P=0.003) before surgery and also predicted magnitude of CABG benefit (P=0.04). Patients with DeltaLVEF -8% or less derived significant survival-prolonging and event-reducing benefit from CABG performed </=1 month after initial testing (P<0.02 for cardiac death and P=0.008 for cardiac events], early CABG versus medical-treatment-only patients); similar benefits were absent among patients with DeltaLVEF more than -8%, and among those in whom CABG was deferred. CONCLUSIONS Assessment of ischemia severity based on LVEF response to exercise enables effective prognostication among patients with 3-vessel CAD and defines the likelihood of life-prolonging and event-reducing benefits from CABG.

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.

Risk stratification in the elderly patient after coronary artery bypass grafting: The prognostic value of radionuclide cineangiography

BackgroundRecent data have shown that assessment of left ventricular function by radionuclide cineangiography (RNCA) predicts survival and cardiac events among non-age-selected patients who have previously undergone coronary artery bypass grafting (CABG). However, the prognostic value of this noninvasive approach is not known for elderly patients who now undergo CABG with progressively increasing frequency and who survive longer because of operation. Such easily applied prognostic indexes may be useful to determine whether survival benefits are likely to be maintained or additional therapy should be considered.Methods and ResultsTo obtain information on factors related to long-term survival and cardiac events among elderly patients after CABG and, specifically, to determine the prognostic implications of left ventricular performance at rest and during exercise for predicting all causes of death, major nonsurgical cardiac events (death or myocardial infarction), and event-free or surgery-free survival, we evaluated the late postoperative course of 41 patients, aged 65 years and older, who had undergone RNCA 1 month or more (mean 2.3±2.4 years; range 0.1 to 9 years) after CABG. Average follow-up among patients with event-free survival was 8.8 years after index radionuclide assessment. During follow-up 13 patients died with no known intercurrent event, five patients had nonfatal myocardial infarctions, and five underwent late (≥3 months after RNCA) repeat CABG or percutaneous transluminal coronary angioplasty. Log-rank comparisons of Kaplan-Meier product limit estimate curves identified only left ventricular ejection fraction at rest as significantly predictive of survival (p<0.04). Patients with left ventricular ejection fraction at rest of less than 45% had a 7.8% average annual mortality risk, which was more than three times that of patients with normal resting function. Statistical trends also were found between mortality rates and completeness of revascularization (p<0.06), major nonsurgical cardiac events and extent of anatomic disease (p<0.08), and event-free or surgery-free survival and our index of completeness of revascularization (p=0.08) and age at index RNCA (p<0.07).ConclusionsAssessment of left ventricular ejection fraction at rest is prognostically useful after CABG among elderly patients. The efficacy and timing of this approach should be confirmed in further investigations with larger and more varied patient subgroups.