Robert C. Schutt

The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: A systematic review and individual patient data meta-analysis

OBJECTIVES The objective of this study was to determine whether measuring post-operative B-type natriuretic peptides (NPs) (i.e., B-type natriuretic peptide [BNP] and N-terminal fragment of proBNP [NT-proBNP]) enhances risk stratification in adult patients undergoing noncardiac surgery, in whom a pre-operative NP has been measured. BACKGROUND Pre-operative NP concentrations are powerful independent predictors of perioperative cardiovascular complications, but recent studies have reported that elevated post-operative NP concentrations are independently associated with these complications. It is not clear whether there is value in measuring post-operative NP when a pre-operative measurement has been done. METHODS We conducted a systematic review and individual patient data meta-analysis to determine whether the addition of post-operative NP levels enhanced the prediction of the composite of death and nonfatal myocardial infarction at 30 and ≥180 days after surgery. RESULTS Eighteen eligible studies provided individual patient data (n = 2,179). Adding post-operative NP to a risk prediction model containing pre-operative NP improved model fit and risk classification at both 30 days (corrected quasi-likelihood under the independence model criterion: 1,280 to 1,204; net reclassification index: 20%; p < 0.001) and ≥180 days (corrected quasi-likelihood under the independence model criterion: 1,320 to 1,300; net reclassification index: 11%; p = 0.003). Elevated post-operative NP was the strongest independent predictor of the primary outcome at 30 days (odds ratio: 3.7; 95% confidence interval: 2.2 to 6.2; p < 0.001) and ≥180 days (odds ratio: 2.2; 95% confidence interval: 1.9 to 2.7; p < 0.001) after surgery. CONCLUSIONS Additional post-operative NP measurement enhanced risk stratification for the composite outcomes of death or nonfatal myocardial infarction at 30 days and ≥180 days after noncardiac surgery compared with a pre-operative NP measurement alone.

Postoperative B-type Natriuretic Peptide for Prediction of Major Cardiac Events in Patients Undergoing Noncardiac Surgery: Systematic Review and Individual Patient Meta-analysis.

Background:It is unclear whether postoperative B-type natriuretic peptides (i.e., BNP and N-terminal proBNP) can predict cardiovascular complications in noncardiac surgery. Methods:The authors undertook a systematic review and individual patient data meta-analysis to determine whether postoperative BNPs predict postoperative cardiovascular complications at 30 and 180 days or more. Results:The authors identified 18 eligible studies (n = 2,051). For the primary outcome of 30-day mortality or nonfatal myocardial infarction, BNP of 245 pg/ml had an area under the curve of 0.71 (95% CI, 0.64–0.78), and N-terminal proBNP of 718 pg/ml had an area under the curve of 0.80 (95% CI, 0.77–0.84). These thresholds independently predicted 30-day mortality or nonfatal myocardial infarction (adjusted odds ratio [AOR] 4.5; 95% CI, 2.74–7.4; P < 0.001), mortality (AOR, 4.2; 95% CI, 2.29–7.69; P < 0.001), cardiac mortality (AOR, 9.4; 95% CI, 0.32–254.34; P < 0.001), and cardiac failure (AOR, 18.5; 95% CI, 4.55–75.29; P < 0.001). For greater than or equal to 180-day outcomes, natriuretic peptides independently predicted mortality or nonfatal myocardial infarction (AOR, 3.3; 95% CI, 2.58–4.3; P < 0.001), mortality (AOR, 2.2; 95% CI, 1.67–86; P < 0.001), cardiac mortality (AOR, 2.1; 95% CI, 0.05–1,385.17; P < 0.001), and cardiac failure (AOR, 3.5; 95% CI, 1.0–9.34; P = 0.022). Patients with BNP values of 0–250, greater than 250–400, and greater than 400 pg/ml suffered the primary outcome at a rate of 6.6, 15.7, and 29.5%, respectively. Patients with N-terminal proBNP values of 0–300, greater than 300–900, and greater than 900 pg/ml suffered the primary outcome at a rate of 1.8, 8.7, and 27%, respectively. Conclusions:Increased postoperative BNPs are independently associated with adverse cardiac events after noncardiac surgery.

Bone Marrow Characteristics Associated With Changes in Infarct Size After STEMI A Biorepository Evaluation From the CCTRN TIME Trial

Rationale: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, selected patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. Objective: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size after ST-segment-elevation–myocardial infarction. Methods and Results: This prospective study comprised patients consecutively enrolled in the CCTRN TIME (Cardiovascular Cell Therapy Research Network Timing in Myocardial Infarction Evaluation) trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac MRI. Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cardiac MRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, −21.0±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31+ BMCs ( P =0.046) and in those with faster BMC growth rates in colony-forming unit Hill and endothelial-colony forming cell functional assays ( P =0.033 and P =0.032, respectively). Conclusions: This study identified BMC characteristics associated with a better clinical outcome in patients with segment-elevation–myocardial infarction and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these patients with segment-elevation–myocardial infarction, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation. Clinical Trial Registration Information: URL: . Unique identifier: [NCT00684021][1]. # Novelty and Significance {#article-title-44} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684021&atom=%2Fcircresaha%2F116%2F1%2F99.atomRationale: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, selected patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. Objective: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size after ST-segment-elevation–myocardial infarction. Methods and Results: This prospective study comprised patients consecutively enrolled in the CCTRN TIME (Cardiovascular Cell Therapy Research Network Timing in Myocardial Infarction Evaluation) trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac MRI. Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cardiac MRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, −21.0±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31+ BMCs (P=0.046) and in those with faster BMC growth rates in colony-forming unit Hill and endothelial-colony forming cell functional assays (P=0.033 and P=0.032, respectively). Conclusions: This study identified BMC characteristics associated with a better clinical outcome in patients with segment-elevation–myocardial infarction and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these patients with segment-elevation–myocardial infarction, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation. Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.

Plasma CXCL12 Levels as a Predictor of Future Stroke

Background and Purpose— The chemokine ligand CXCL12 is constitutively expressed in the bone marrow and other tissues including the brain endothelium and is responsible for regulating the trafficking of bone marrow progenitor cells. CXCL12 has been shown to play a significant role in animal models of ischemic stroke but its role in human stroke is unclear. The aim of this study was to test the hypothesis that elevated circulating baseline CXCL12 levels are associated with subsequent stroke. Methods— We prospectively collected demographic and angiographic data from consecutive patients referred for elective coronary angiography. Before coronary angiography a peripheral blood sample was collected for subsequent measurement of CXCL12. One-year stroke risk was calculated using the Framingham Risk Profile. Clinical follow-up was performed at 6 months and 1 year. Results— Of 206 subjects enrolled, 10 (4.9%) sustained an ischemic stroke over the 1year follow-up. There were no significant differences in baseline clinical characteristics or angiographic findings. However, median CXCL12 levels were significantly higher in those who sustained an ischemic stroke compared with those who did not (10 856 pg/mL versus 2241 pg/mL, P=0.007). The time to stroke distribution between subjects with baseline CXCL12 levels ≥10 421 pg/mL and those with baseline CXCL12 levels <10 421 pg/mL was significantly different (log rank P<0.001). The weighted Cox proportional hazard model demonstrated that baseline CXCL12 levels ≥10 421 pg/mL were significantly associated with ischemic stroke at follow-up (hazard ratio, 15.29; 95% CI, 3.05–76.71). Conclusions— Plasma CXCL12 levels may represent a novel biomarker of future ischemic stroke.

Identification of bone marrow cell subpopulations associated with improved functional outcomes in patients with chronic left ventricular dysfunction: An embedded cohort evaluation of the FOCUS-CCTRN trial

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4+ BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy—even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.

Additive prognostic value of coronary artery calcium score over coronary computed tomographic angiography stenosis assessment in symptomatic patients without known coronary artery disease.

The objective of this study was to examine the additive prognostic performance of coronary artery calcium score (CACS) over coronary computed tomography angiography (CCTA) stenosis assessment in symptomatic patients suspected for coronary artery disease (CAD) undergoing CCTA. A total of 805 symptomatic patients without known history of CAD who underwent coronary evaluation by multidetector cardiac CT were analyzed. Mean age of the cohort was 58 ± 13 years. A total of 44% (354 of 805) of the patients had a 0 CACS, 27% (215 of 805) had CACS 1 to 100, 14% (111 of 805) had CACS 101 to 400, and 15% (125 of 805) had CACS >400. CCTA showed normal coronary arteries in 43% (349 of 805) of patients, ≤50% stenosis in 42% (333 of 805), and >50% stenosis in 15% (123 of 805). Patients were followed for 2.3 ± 0.9 years. Major adverse cardiac event (MACE) was defined as cardiac death, nonfatal myocardial infarction, and late coronary revascularization. Overall incidence of MACE was 1.4% per year. Both CACS and CCTA stenosis were independently associated with increased MACE (p <0.05 for both). Addition of CACS into the model with clinical risk factors and CCTA stenosis significantly improved predictive performance for MACE from the model with clinical risk factors and CCTA stenosis only (global chi-square score 108 vs 70; p = 0.019). In conclusion; in symptomatic patients without known CAD, both CACS and CCTA stenosis were independently associated with increased cardiac events, and performing non-contrast-enhanced CACS evaluation in addition to contrast-enhanced CCTA improved predictive ability for future cardiac events compared to CCTA stenosis assessment alone.

Doege-Potter syndrome presenting with hypoinsulinemic hypoglycemia in a patient with a malignant extrapleural solitary fibrous tumor: a case report

IntroductionDoege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. This tumor causes hypoglycemia by the secretion of a prohormone form of insulin-like growth factor II. We describe the diagnosis and management of Doege-Potter syndrome and the use of transarterial chemoembolization in a patient with a malignant extrapleural solitary fibrous tumor.Case presentationOur patient was a 64-year-old Caucasian woman who initially presented with urinary incontinence and was found to have a 14.5×9.0×9.0cm retroperitoneal solitary fibrous tumor compressing her bladder. Her tumor was surgically resected but recurred with multiple hepatic metastatic lesions. The hepatic metastases progressed despite systemic chemotherapy and treatment with doxorubicin transarterial chemoembolization. Her course was complicated by the development of recurrent fasting hypoglycemia, most likely secondary to Doege-Potter syndrome. Her hypoglycemia was managed with corticosteroid therapy and frequent scheduled nutrient intake overnight.ConclusionsThe rarity of hepatic solitary fibrous tumors and consequent lack of controlled trials make this report significant in that it describes the diagnostic approach to Doege-Potter syndrome, describes our experience with the use of doxorubicin transarterial chemoembolization, and presents management options for tumor-associated hypoglycemia in the case of extensive disease not amenable to surgical resection.

Circulating Biomarkers to Identify Responders in Cardiac Cell therapy

Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes. We investigated the clinical value of circulating proteins in outcome prediction using significance testing, partial least squares discriminant analysis, and receiver operating characteristic (ROC) analysis. Responders had higher biomarker levels (76–94% elevated) than non-responders. Several biomarkers had values that differed significantly (P < 0.05) between responders and non-responders including stem cell factor, platelet-derived growth factor, and interleukin-15. We then used these lead candidates for ROC analysis and found multiple biomarkers with values areas under the curve >0.70 including interleukin 15. These biomarkers were not involved in the placebo-treated subjects suggesting that they may have predictive power. We conclude that plasma profiling after STEMI may help identify patients with a greater likelihood of response to cell-based treatment. Prospective trials are needed to assess the predictive value of the circulating biomarkers.

Vortex Formation Time Index in Patients With Hypertrophic Cardiomyopathy

Vortex ring formation in early diastole helps with left ventricular (LV) filling without an increase in left atrial (LA) pressure. Vortex formation time (VFT) is a dimensionless parameter derived from LV geometry and indexes of LV systolic and diastolic performance [(1)][1]. The optimal range was

Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial.

BACKGROUND Although several preclinical studies have shown that bone marrow cell (BMC) transplantation promotes cardiac recovery after myocardial infarction, clinical trials with unfractionated bone marrow have shown variable improvements in cardiac function. METHODS To determine whether in a population of post-myocardial infarction patients, functional recovery after BM transplant is associated with specific BMC subpopulation, we examined the association between BMCs with left ventricular (LV) function in the LateTIME-CCTRN trial. RESULTS In this population, we found that older individuals had higher numbers of BM CD133(+) and CD3(+) cells. Bone marrow from individuals with high body mass index had lower CD45(dim)/CD11b(dim) levels, whereas those with hypertension and higher C-reactive protein levels had higher numbers of CD133(+) cells. Smoking was associated with higher levels of CD133(+)/CD34(+)/VEGFR2(+) cells and lower levels of CD3(+) cells. Adjusted multivariate analysis indicated that CD11b(dim) cells were negatively associated with changes in LV ejection fraction and wall motion in both the infarct and border zones. Change in LV ejection fraction was positively associated with CD133(+), CD34(+), and CD45(+)/CXCR4(dim) cells as well as faster BMC growth rates in endothelial colony forming assays. CONCLUSIONS In the LateTIME population, BM composition varied with patient characteristics and treatment. Irrespective of cell therapy, recovery of LV function was greater in patients with greater BM abundance of CD133(+) and CD34(+) cells and worse in those with higher levels of CD11b(dim) cells. Bone marrow phenotype might predict clinical response before BMC therapy and administration of selected BM constituents could potentially improve outcomes of other future clinical trials.