Right Ventricular Dysfunction and Short-Term Outcomes Following Left-Sided Valvular Surgery: An Echocardiographic Study.

Background The prognostic value of echocardiographic evaluation of right ventricular (RV) function in patients undergoing left-sided valvular surgery has not been well described. The objective of this study is to determine the role of broad echocardiographic assessment of RV function in predicting short-term outcomes after valvular surgery. Methods and Results Preoperative echocardiographic data, perioperative adverse outcomes, and 30-day mortality were analyzed in patients who underwent left-sided valvular surgery from 2006 to 2014. Echocardiographic parameters used to evaluate RV function include RV fractional area change, tricuspid annular plane systolic excursion, systolic movement of the RV lateral wall using tissue Doppler imaging (S'), RV myocardial performance index, and RV dP/dt. Subjects with at least 3 abnormal parameters out of the 5 aforementioned indices were defined as having significant RV dysfunction. The study included 269 patients with valvular surgery (average age: 67±15, 60.6% male, 148 aortic, and 121 mitral). RV dysfunction was found in 53 (19.7%) patients; 30-day mortality occurred in 20 patients (7.5%). Compared with normal RV function, patients with RV dysfunction had higher 30-day mortality (22.6% versus 3.8%; P=0.01) and were at risk for developing multisystem failure/shock (13.2% versus 3.2%; P=0.01). Multivariate analyses showed that preexisting RV dysfunction was the strongest predictor of increased 30-day mortality (odds ratio: 3.5; 95% CI, 1.1-11.1; P<0.05). Conclusions Preoperative RV dysfunction identified by comprehensive echocardiographic assessment is a strong predictor of adverse outcomes following left-sided valvular surgery.

Orthopedic Principles to Facilitate Enhanced Recovery After Cardiac Surgery.

Enhanced recovery after surgery (ERAS) protocols recognize early postoperative mobilization as a driver of faster postoperative recovery, return to normal activities, and improved long-term patient outcomes. For patients undergoing open cardiac surgery, an opportunity for facilitating earlier mobilization and a return to normal activity lies in the use of improved techniques to stabilize the sternal osteotomy. By following the key orthopedic principles of approximation, compression, and rigid fixation, a more nuanced approach to sternal precaution protocols is possible, which may enable earlier patient mobilization, physical rehabilitation, and recovery.

Pre-operative right ventricular echocardiographic parameters associated with short-term outcomes and long-term mortality after CABG.

Background This analysis aims to assess the prognostic value of pre-operative right ventricular echocardiographic parameters in predicting short-term adverse outcomes and long-term mortality after coronary artery bypass graft (CABG). Methods Study design: Observational retrospective cohort. Pre-operative echocardiographic data, perioperative adverse outcomes (POAO) and long-term mortality were retrospectively analyzed in 491 patients who underwent isolated CABG at a single academic center between 2006 and 2014. Results Average age of enrolled subjects was 66 ± 11.5 years with majority being male (69%). 227/491 patients had 30 days POAO (46%); most common being post-operative atrial fibrillation (27.3%) followed by prolonged ventilation duration (12.7%). On multivariate analysis, left atrial volume index ≥42 mL/m2 (LAVI) (OR (95% CI): 1.98 (1.03-3.82), P = 0.04), mitral E/A >2 (1.97 (1.02-3.78), P = 0.04), right atrial size >18 cm2 (1.86 (1.14-3.05), P = 0.01), tricuspid annular plane systolic excursion (TAPSE) <16 mm (1.8 (1.03-3.17), P = 0.04), right ventricular systolic pressure (RVSP) ≥36 mmHg (pulmonary hypertension) (1.6 (1.03-2.38), P = 0.04) and right ventricle myocardial performance index (RVMPI) >0.55 (1.58 (1.01-2.46), P = 0.04) were found to be associated with increased 30-day POAO. On 3.5-year follow-up, cumulative survival was decreased in patients with myocardial performance index (MPI) ≥0.55 (log rank: 4.5, P = 0.034) and in patients with mitral valve E/e' ≥14 (log rank: 4.9, P = 0.026). Conclusion Pre-operative right ventricle dysfunction (RVD) is associated with increased perioperative complications. Furthermore, pre-operative RVD and increased left atrial pressures are associated with long-term mortality post CABG.

The Incremental Value of Three or More Arterial Grafts in CABG: The Effect of Native Vessel Disease.

BACKGROUND: We investigated whether extended arterial grafting with three or more arterial grafts in patients with a left internal thoracic artery to left anterior descending artery graft improves survival in coronary artery bypass graft surgery patients and whether its effects will depend on the extent of coronary artery disease; specifically three-vessel disease (3VD) versus two-vessel disease (2VD). METHODS: Fifteen-year mortality was analyzed in 11,931 patients with multivessel disease and primary isolated left internal thoracic artery to left anterior descending artery coronary artery bypass graft surgery with 2 or more grafts. Patients were aged 64.3 ± 10.5 years; 3,484 (29.2%) were women; 2,532 (21.2%) had 2VD and 9,399 (78.8%) had 3VD. Patients were grouped into one single-artery group (n = 6,782, 56.9%; reference group), and two multiple artery groups: two arteries (n = 3,678, 30.8%) and three arteries (n = 1,471, 12.3%). Long-term survival was compared by Kaplan-Meier estimates. Risk-adjusted mortality hazard ratio (HR) with 95% confidence interval (CI) were derived by covariate adjusted Cox regression to quantify multiple artery effects versus one artery in the overall cohort and separately among patients with 2VD and 3VD. RESULTS: Radial artery (94%) and right internal thoracic artery (6%) conduits were used for additional arterial grafts. For the entire multivessel cohort, increasing number of arterial grafts was associated with incrementally improved 15-year survival (two arteries HR 0.85, 95% CI: 0.78 to 0.92; three arteries HR 0.75, 95% CI: 0.65 to 0.85). The three arteries versus two arteries comparison was consistent, even if not significant (HR 0.89, 95% CI: 0.77 to 1.03). The benefits derived from additional arterial grafts were more pronounced in case of 3VD (two arteries HR 0.84 95% CI: 0.76 to 0.92; three arteries HR 0.73, 95% CI: 0.63 to 0.84), without survival benefit with 2VD. CONCLUSIONS: Our results support the use of extended arterial grafting to maximize long-term coronary artery bypass graft surgery patient survival, especially for 3VD patients.

The effect of completeness of revascularization during CABG with single versus multiple arterial grafts.

INTRODUCTION: Incomplete coronary revascularization is associated with suboptimal outcomes. We investigated the long-term effects of Incomplete, Complete, and Supra-complete revascularization and whether these effects differed in the setting of single-arterial and multi-arterial coronary artery bypass graft (CABG). METHODS: We analyzed 15-year mortality in 7157 CABG patients (64.1 ± 10.5 years; 30% women). All patients received a left internal thoracic artery to left anterior descending coronary artery graft with additional venous grafts only (single-arterial) or with at least one additional arterial graft (multi-arterial) and were grouped based on a completeness of revascularization index (CRI = number of grafts minus the number of diseased principal coronary arteries): Incomplete (CRI ≤ -1 [N = 320;4.5%]); Complete (CRI = 0 [N = 2882;40.3%]; reference group); and two Supra-complete categories (CRI = +1[N = 3050; 42.6%]; CRI ≥ + 2 [N = 905; 12.6%]). Risk-adjusted mortality hazard ratios (AHR) were calculated using comprehensive propensity score adjustment by Cox regression. RESULTS: Incomplete revascularization was rare (4.5%) but associated with increased mortality in all patients (AHR [95% confidence interval] = 1.53 [1.29-1.80]), those undergoing single-arterial CABG (AHR = 1.27 [1.04-1.54]) and multi-arterial CABG (AHR = 2.18 [1.60-2.99]), as well as in patients with 3-Vessel (AHR = 1.37 [1.16-1.62]) and, to a lesser degree, with 2-Vessel (AHR = 1.67 [0.53-5.23]) coronary disease. Supra-complete revascularization was generally associated with incrementally decreased mortality in all patients (AHR [CRI = +1] = 0.94 [0.87-1.03]); AHR [CRI ≥ +2] = 0.74 [0.64-0.85]), and was driven by a significantly decreased mortality risk in single-arterial CABG (AHR [CRI = +1] = 0.90 [0.81-0.99]; AHR [CRI ≥ +2] = 0.64 [0.53-0.78]); and 3-Vessel disease patients (AHR [CRI = +1] = 0.94 [0.86-1.04]; and AHR [CRI ≥ +2] = 0.75 [0.63-0.88]) with no impact in multi-arterial CABG (AHR [CRI = +1] = 1.07 [0.91-1.26]; AHR [CRI ≥ +2] = 0.93 [0.73-1.17]). CONCLUSIONS: Incomplete revascularization is associated with decreased late survival, irrespective of grafting strategy. Alternatively, supra-complete revascularization is associated with improved survival in patients with 3-Vessel CAD, and in single-arterial but not multi-arterial CABG.

Evidence and temporality of the obesity paradox in coronary bypass surgery: an analysis of cause-specific mortality.

OBJECTIVES: We evaluated the presence of an 'obesity paradox' in coronary artery bypass grafting (CABG) patients, determined its time course and ascertained whether it is associated with improved cardiovascular (CV) survival versus non-CV survival. METHODS: A retrospective analysis of 3 prospectively collected databases was conducted. A fifteen-year Kaplan-Meier analysis in 7091 CABG patients was performed and repeated in 5 body mass index [BMI (kg/m2)] cohorts [Normal (18.5-24.99 kg/m2), Overweight (25-29.99 kg/m2), Obese I (30-34.99 kg/m2), Obese II (35-39.99 kg/m2) and Obese III (≥40 kg/m2)]. Mortality hazard ratios {HR [95% confidence interval (CI)]} were derived using comprehensive multivariable competing risk Cox regression, accounting for BMI categories for overall (0-15), Early (0-1), Intermediate (1-8) and Late (8-15) postoperative years, to relax the proportional hazards assumption. The regression was repeated using BMI as a continuous variable. Mortality was classified into any, CV and non-CV. RESULTS: Obese patients were younger with more comorbidities. Fifteen-year survival was improved in the Overweight and Obese I groups (P < 0.001). Adjusted 15-year mortality was reduced in the Overweight [HR (95% CI) = 0.88 (0.79-0.98)] and Obese I [HR = 0.88 (0.78-0.99)] groups driven by improved CV and non-CV survival. This trend was noted in the early (Overweight) and intermediate postoperative periods (Overweight and Obese I) with no significance in the late period. Higher mortality in the Obese III [HR = 1.28 (1.06-1.55)] group was driven by a decreased CV survival. Using BMI as a continuous variable, a BMI of 29 kg/m2 was associated with optimal survival. CONCLUSIONS: We identified a protective partial obesity paradox in the early and intermediate postoperative periods among Overweight and mildly obese (Obese I) patients with improved CV and non-CV survival. The morbidly obese (the Obese III group) had higher early and late CV mortality.

Effectiveness of radial artery-based multiarterial coronary artery bypass grafting: Role of body habitus.

BACKGROUND: The multiarterial grafting survival advantage noted in the overall population undergoing coronary artery bypass grafting is not well defined in the obese. We investigated the early to late survival effects of the radial artery in left internal thoracic artery-based multiarterial bypass grafting (radial artery-multiarterial bypass grafting) versus single arterial bypass grafting (left internal thoracic artery-single arterial bypass grafting) in obese patients. METHODS: We analyzed 15-year Kaplan-Meier survival in 6102 patients receiving primary, left internal thoracic artery-based coronary artery bypass grafting with 2 or more grafts divided into body mass index groups: nonobese (<30 kg/m2) and all-obese, comprised of mildly obese (30-35 kg/m2) and morbidly obese (>35 kg/m2). Risk-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of radial artery-multiarterial bypass grafting versus left internal thoracic artery-single arterial bypass grafting were derived via Cox regression and applied separately for early (<0.5 years), intermediate (0.5-5 years), and late (5-15 years) follow-up in each body mass index cohort. Propensity score matching between radial artery-multiarterial bypass grafting and left internal thoracic artery-single arterial bypass grafting cohorts within the body mass index groups was performed as a corroborating analysis. RESULTS: Radial artery-multiarterial bypass grafting was more frequently used in obese patients who were younger (62 ± 10 years; mild/morbid: 45.4%/54.4% radial artery-multiarterial bypass grafting) compared with nonobese patients (66 ± 10 years; 37.4% radial artery-multiarterial bypass grafting). Unadjusted 15-year survival was significantly better for radial artery-multiarterial bypass grafting in all body mass index groups. Multivariate analysis showed a survival benefit of radial artery-multiarterial bypass grafting over the entire 0- to 15-year study period in the all-obese cohort (HR, 0.85; 95% CI, 0.74-0.98) and was more pronounced in the mildly obese (HR, 0.79; 95% CI, 0.66-0.96) versus morbidly obese (HR, 0.88; 95% CI, 0.69-1.13). The radial artery-multiarterial bypass grafting survival benefit was realized between 0.5 and 5 years postoperatively and was comparable for all-obese (HR, 0.69; 95% CI, 0.51-0.94) and nonobese (HR, 0.68; 95% CI, 0.52-0.88) groups. Propensity score matching was confirmatory. CONCLUSIONS: Radial artery-multiarterial bypass grafting confers a long-term survival advantage in both obese and nonobese patients.

Operative Outcomes of Multiple-Arterial Versus Single-Arterial Coronary Bypass Grafting.

BACKGROUND: More than 90% of coronary artery bypass grafting (CABG) is performed with a single-arterial bypass graft (SABG), based on the left internal thoracic artery (ITA) with supplemental vein grafts. This practice, often justified by safety concerns with multiple-arterial grafting (MABG), defies evidence of improved late survival achieved with bilateral ITA (BITA-MABG) or left ITA plus radial artery (RA-MABG). We hypothesized that MABG and SABG are equally safe. METHODS: We analyzed The Society of Thoracic Surgeons National Database (2004 to 2015) to assess the operative safety of BITA-MABG (n = 73,054) and RA-MABG (n = 97,623) vs SABG (n = 1,334,511). Primary end points were operative (30-day or same hospitalization) mortality (OM) and deep sternal wound infections (DSWI). Risk-adjusted odds ratios (AOR) and 95% confidence intervals (CIs) were derived from by logistic regression with sensitivity analyses in multiple subcohorts including MABG use rate. RESULTS: SABG (73.8% men; median age, 66 years), BITA-MABG (85.1% men; median age, 59 years), and RA-MABG (82.5% men; median age, 61 years) showed distinctly different patient characteristics. Compared with SABG (1.91% OM; 0.73% DSWI), observed OM was lower for BITA-MABG (1.19%, p < 0.001) and RA-MABG (1.19%, p < 0.001). DSWI was higher among BITA-MABG (1.08%, p < 0.001) and similar for RA-MABG (0.71%, p = 0.55). BITA-MABG showed marginally increased, likely not clinically significant, OM (AOR, 1.14; 95% CI, 1.00 to 1.30; p = 0.05) and doubled DSWI (AOR, 2.09; 95% CI, 1.80 to 2.43; p < 0.001). RA-MABG had similar OM (AOR, 1.01; 95% CI, 0.89 to 1.15; p = 0.85) and DSWI (AOR, 0.97; 95% CI, 0.83 to 1.13; p = 0.70). Results were consistent across multiple subcohorts. A U-shaped OM vs BITA use relation was documented, with worse OM at hospitals with low (<5%: AOR, 1.38; 95% CI, 1.18 to 1.61; p < 0.001) and high (≥40%: AOR, 1.31; 95% CI, 1.00 to 1.70; p = 0.049) BITA use. CONCLUSIONS: MABG in the United States is associated with OM comparable to SABG and increased DSWI risk with BITA-MABG. Our findings highlight the importance of surgeon and institutional experience and careful patient selection for BITA-MABG. Our short-term results should not in any way dissuade the use of MABG, given its well-established long-term survival advantage.

Incremental Value of Increasing Number of Arterial Grafts: The Effect of Diabetes Mellitus.

BACKGROUND: Multiarterial coronary grafting with two arterial grafts leads to improved survival compared with conventional single artery based on left internal thoracic artery to left anterior descending artery and saphenous vein grafts. We investigated whether extending arterial grafting to three or more arterial grafts further improves survival, and whether such a benefit is modified by diabetes mellitus. METHODS: We analyzed 15-year coronary artery bypass graft surgery mortality data in 11,931 patients (age 64.3 ± 10.5 years; 3,484 women [29.2%]; 4,377 [36.7%] with diabetes mellitus) derived from three US institutions (1994 to 2011). All underwent primary isolated left internal thoracic artery to left anterior descending artery grafting with at least two grafts: one artery (n = 6,782; 56.9%); two arteries (n = 3,678; 30.8%); or three or more arteries (n = 1,471; 12.3%). Long-term survival was estimated by Kaplan-Meier methods. Propensity score matching and comprehensive covariate adjustment (Cox regression) were used to derive long-term risk-adjusted hazard ratio (HR) with 95% confidence interval (CI) for increasing number of arterial grafts in the overall cohort and for diabetes and no-diabetes cohorts. RESULTS: Radial artery (94%) and right internal thoracic artery (6%) were used as additional arterial grafts. Multivariate analysis in all patients showed that diabetes was associated with decreased survival (HR 1.43, 95% CI: 1.34 to 53), whereas increasing number of arterial grafts was associated with decreased mortality (one artery HR 1.0 [reference]; two arteries HR 0.87, 95% CI: 0.80 to 0.95; and three arteries HR 0.83, 95% CI: 0.72 to 0.95). Pairwise comparisons also showed an incremental benefit of additional arterial grafts: two arteries versus one artery, HR 0.89 (95% CI: 0.80 to 0.98); and three arteries versus one artery, HR 0.80 (95% CI: 0.68 to 0.94). A three-artery versus two-artery survival advantage trend was also noted, but was not significant in either the overall study cohort (HR 0.90, 95% CI: 0.75 to 1.07), the diabetes cohort (HR 0.79, 95% CI: 0.60 to 1.03), or the no-diabetes cohort (HR 01.00, 95% CI: 0.79 to 1.26). Among diabetes patients, the survival advantage of two arteries versus one artery was modest (HR 0.96, 95% CI: 0.72 to 1.11), whereas it was significant for three arteries versus one artery (HR 0.74, 95% CI: 0.58 to 0.96). Analyses of propensity matched subcohorts were also consistent. CONCLUSIONS: Increasing number of arterial grafts improves long-term survival and supports extended use of arterial grafts in coronary artery bypass graft surgery, irrespective of diabetes status.

Effect of new-onset atrial fibrillation on cause-specific late mortality after coronary artery bypass grafting surgery.

OBJECTIVES: Postoperative atrial fibrillation (POAF) is a common complication after coronary artery bypass grafting. Although transient, POAF is linked to increased late mortality. We hypothesized that POAF increases late cerebrovascular (CeV) and composite cerebrovascular/cardiovascular/vascular (CV* = CeV + CV + Other-V) but not non-cardiovascular (Non-CV) mortality. METHODS: We analysed 8807 non-salvage coronary artery bypass grafting patients (1994-2011). Fifteen-year and time-segmented (early, 0-1 year; intermediate, 1-6 years and late, 6-15 years) all-cause and cause-specific mortality were compared for POAF versus No-POAF patients. Corresponding POAF versus No-POAF adjusted hazard ratios [AHRs (95% confidence interval, CI)] were derived using the competing risk Cox regression. RESULTS: POAF occurred in 1992 (23%) patients. Complications other than POAF occurred in 1875 (21%) patients but were more frequent among POAF patients (31% vs 18%; P < 0.001). Overall mean follow-up was 9 ± 4 years. POAF patients had a higher 15-year unadjusted mortality (53% vs 39%; P < 0.001) and were consequently associated with higher adjusted all-cause [AHR (95% CI) = 1.23 (1.14-1.33)] and composite cardiovascular [CV*: AHR (95% CI) = 1.15 (1.02-1.30)] mortality. The trends towards a higher 15-year CeV [AHR (95% CI) = 1.34 (0.94-1.91)] and Non-CV [AHR (95% CI) = 1.12 (0.99-1.26)] mortality were not significant. Time-segmented analyses showed that (i) POAF increased all-cause mortality early, and this persisted in the intermediate and late periods and (ii) CeV [AHR (95% CI) = 2.14 (1.14-4.04)] and CV* [AHR (95% CI) = 1.31 (1.06-1.62)] mortality rates were increased in the intermediate but not in the early or late periods. Non-CV mortality was similar in POAF and No-POAF for all time intervals. These findings were corroborated in propensity-matched sub-cohorts and in sensitivity analyses in patients free of any other complication. CONCLUSIONS: POAF is associated with worse long-term survival principally driven by increased intermediate-term cerebrovascular and cardiovascular mortality, while Non-CV mortality was similar.

Variation in Warfarin Use at Hospital Discharge After Isolated Bioprosthetic Mitral Valve Replacement: An Analysis of the Society of Thoracic Surgeons Adult Cardiac Surgery Database.

BACKGROUND: Anticoagulation with warfarin following bioprosthetic mitral valve replacement (BMVR) is recommended by multiple practice guidelines. We assessed practice variability and patient characteristics associated with warfarin prescription following BMVR. METHODS: We analyzed 7,637 patients in the Society of Thoracic Surgeons Database (January 1, 2008 to June 30, 2011) who were discharged following isolated primary nonemergent BMVR. Patients requiring preoperative warfarin, those with preoperative atrial fibrillation, or those with a contraindication to warfarin were excluded. The association between patient, hospital, and surgeon characteristics and warfarin prescription were evaluated. RESULTS: Fifty-eight percent of this cohort (median age, 66 years; female sex, 58.7%) was prescribed warfarin. Patients receiving warfarin were older (67 vs 65 years; P < .0001), were less likely to have had preoperative stroke (9.3% vs 12.1%; P < .001), CHF (51.4% vs 54.1%; P < .02), or dialysis (4.9% vs 9.0%; P < 0.001), and had a longer postoperative length of stay (8.0 vs 7.0 days; P < 0.01). Warfarin was prescribed less often for patients with postoperative GI events (44.4% vs 55.6%; P < .001) but more often for patients with postoperative myocardial infarction (75.8% vs 24.2%; P < .001) or new atrial fibrillation (68% vs 32%; P < .001) and those requiring blood transfusions intraoperatively (55.7% vs 44.3%; P < .001) or postoperatively (57% vs 43%; P < .03). Similar rates of warfarin prescription were observed in patients requiring reoperation for bleeding (54.9% vs 45.1%; P = .20) and those with postoperative stroke (53.6 % vs 46.4 %; P = .30). After adjusting for patient characteristics, significant surgeon and hospital variation in warfarin prescription at hospitals was observed. CONCLUSIONS: Although patient characteristics and postoperative events may be associated with the prescription of warfarin following BMVR, substantial surgeon and hospital variability remains. This variability largely ignores the established practice guidelines and warrants further study to define the optimal anticoagulation strategy in patients undergoing BMVR.

Diaphragm Abnormalities in Patients with End-Stage Heart Failure: NADPH Oxidase Upregulation and Protein Oxidation.

Patients with heart failure (HF) have diaphragm abnormalities that contribute to disease morbidity and mortality. Studies in animals suggest that reactive oxygen species (ROS) cause diaphragm abnormalities in HF. However, the effects of HF on ROS sources, antioxidant enzymes, and protein oxidation in the diaphragm of humans is unknown. NAD(P)H oxidase, especially the Nox2 isoform, is an important source of ROS in the diaphragm. Our main hypothesis was that diaphragm from patients with HF have heightened Nox2 expression and p47phox phosphorylation (marker of enzyme activation) that is associated with elevated protein oxidation. We collected diaphragm biopsies from patients with HF and brain-dead organ donors (controls). Diaphragm mRNA levels of Nox2 subunits were increased 2.5-4.6-fold over controls (p < 0.05). Patients also had increased protein levels of Nox2 subunits (p47phox, p22phox, and p67phox) and total p47phox phosphorylation, while phospho-to-total p47phox levels were unchanged. The antioxidant enzyme catalase was increased in patients, whereas glutathione peroxidase and superoxide dismutases were unchanged. Among markers of protein oxidation, carbonyls were increased by ~40% (p < 0.05) and 4-hydroxynonenal and 3-nitrotyrosines were unchanged in patients with HF. Overall, our findings suggest that Nox2 is an important source of ROS in the diaphragm of patients with HF and increases in levels of antioxidant enzymes are not sufficient to maintain normal redox homeostasis. The net outcome is elevated diaphragm protein oxidation that has been shown to cause weakness in animals.

A Protocol for Collecting Human Cardiac Tissue for Research.

This manuscript describes a protocol at the University of Kentucky that allows a translational research team to collect human myocardium that can be used for biological research. We have gained a great deal of practical experience since we started this protocol in 2008, and we hope that other groups might be able to learn from our endeavors. To date, we have procured ~4000 samples from ~230 patients. The tissue that we collect comes from organ donors and from patients who are receiving a heart transplant or a ventricular assist device because they have heart failure. We begin our manuscript by describing the importance of human samples in cardiac research. Subsequently, we describe the process for obtaining consent from patients, the cost of running the protocol, and some of the issues and practical difficulties that we have encountered. We conclude with some suggestions for other researchers who may be considering starting a similar protocol.

Equipoise between radial artery and right internal thoracic artery as the second arterial conduit in left internal thoracic artery-based coronary artery bypass graft surgery: a multi-institutional study†.

OBJECTIVES: Multiple arterial coronary artery grafting (MABG) improves long-term survival compared with single arterial CABG (SABG), yet the best second arterial conduit to be used with the left internal thoracic artery (LITA) remains undefined. Outcomes in patients grafted with radial artery (RA-MABG) versus right internal thoracic artery (RITA-MABG) as the second arterial graft were compared with SABG. METHODS: Multi-institutional, retrospective analysis of non-emergent isolated LITA to left anterior descending coronary artery CABG patients was performed using institutional Society of Thoracic Surgeon National Adult Cardiac Surgery Databases. 4484 (54.5%) SABG [LITA ± saphenous vein grafts (SVG)], 3095 (37.6%) RA-MABG (RA ± SVG) and 641 (7.9%) RITA-MABG (RITA ± SVG) patients were included. The RITA was used as a free (68%) or in situ (32%) graft. RA grafts were principally anastomosed to the ascending aorta. Long-term survival was ascertained from US Social Security Death Index and institutional follow-up. Triplet propensity matching and covariate-adjusted multivariate logistic regression were used to adjust for baseline differences between study cohorts. RESULTS: Compared with the SABG cohort, the RITA-MABG cohort was younger (58.6 ± 10.2vs65.9 ± 10.4, P < 0.001), had a higher prevalence of males (87% vs 65%, P < 0.001) and was generally healthier (MI: 36.7% vs 56.7%, P < 0.001, smoking: 56.8% vs 61.1%, IDDM: 3.0% vs 14.4%, CVA: 2.6% vs 10.0%). The RA-MABG cohort was generally characterized by a risk profile intermediate to that of SABG and RlTA-MABG. Unadjusted 5-, 10- and 15-year survival rates were best in RITA-MABG (95.2%, 89% and 82%), intermediate in RA-MABG (89%, 74%, 57%) and worst in SABG (82%, 61% and 44%) cohorts (all P < 0.001). Propensity matching yielded 551 RA-MABG, RITA-MABG and SABG triplets, which showed similar 30-day mortality. Late survival (16 years) was equivalent in the RA-MABG and RITA-MABG cohorts [68.2% vs 66.7%, P = 0.127, hazard ratio (HR) = 1.28 (0.96-1.71)] and both significantly better than SABG (61.1%). The corresponding SABG versus RITA-MABG and SABG versus RA-MABG HRs (95% confidence interval) were 1.52 (1.18-1.96) and 1.31 (1.01-1.69) with P < 0.002 and P = 0.038, respectively. CONCLUSIONS: RA-MABG or RITA-MABG equally improve long-term survival compared with SABG and thus should be embraced by the Heart Team as the therapy of choice in LITA-based coronary artery bypass surgery.

Multi Versus Single Arterial Coronary Bypass Graft Surgery Across the Ejection Fraction Spectrum.

BACKGROUND: Left internal thoracic artery (LITA) and radial artery (RA) multi-arterial CABG (MABG) is generally associated with improved long-term survival compared with traditional LITA and saphenous vein single arterial CABG (SABG). We examined the hypothesis that this multi-arterial survival advantage persists irrespective of left ventricular ejection fraction (LVEF). METHODS: We retrospectively analyzed the primary, non-salvage multi-graft CABG experience (n = 11,261; 64.4 ± 10.4 years, 70.4% men) from 2 institutions (1995 to 2011). Risk-adjusted 15-year survival was pairwise compared for the MABG versus SABG grafting approaches within 3 LVEF subcohorts (>0.50, n = 4,833 [44% MABG]; 0.36 to 0.50, n = 4,465 [39% MABG]; and ≤ 0.35, n = 1,963 [35% MABG]) using propensity-matched and covariate adjusted Cox regression (all patients) comparisons. RESULTS: Propensity matching yielded 1,317 (LVEF > 0.50), 1,179 (LVEF, 0.36 to 0.50), and 470 (LVEF ≤ 0.35) well-matched grafting method pairs. Acute perioperative mortality was equivalent between MABG and SABG within each LVEF group, but increased with decreasing LVEF. MABG was uniformly associated with better 15-year survival compared with SABG for all LVEF categories. The associated matched-adjusted hazard ratios (95% confidence intervals) were consistent across EF groups at 0.79 (0.68 to 0.93), 0.80 (0.69 to 0.93), and 0.82 (0.66 to 1.0), respectively. Covariate adjusted HR in all patients concurred with matched results. CONCLUSIONS: MABG results in significantly enhanced long-term survival compared with LITA/SVG SABG regardless of the degree of LV dysfunction. These results favor MABG as the therapy of choice in patients with LV dysfunction.

Heart Failure in Non-Caucasians, Women, and Older Adults: A White Paper on Special Populations From the Heart Failure Society of America Guideline Committee.

The presentation, natural history, clinical outcomes, and response to therapy in patients with heart failure differ in some ways across populations. Women, older adults, and non-Caucasian racial or ethnic groups compose a substantial proportion of the overall heart failure population, but they have typically been underrepresented in clinical trials. As a result, uncertainty exists about the efficacy of some guideline-directed medical therapies and devices in specific populations, which may result in the under- or overtreatment of these patients. Even when guideline-based treatments are prescribed, socioeconomic, physical, or psychologic factors may affect non-Caucasian and older adult patient groups to a different extent and affect the application, effectiveness, and tolerability of these therapies. Individualized therapy based on tailored biology (genetics, proteomics, metabolomics), socioeconomic and cultural considerations, and individual goals and preferences may be the optimal approach for managing diverse patients. This comprehensive approach to personalized medicine is evolving, but in the interim, the scientific community should continue efforts focused on intensifying research in special populations, prescribing guideline-directed medical therapy unless contraindicated, and implementing evidence-based strategies including patient and family education and multidisciplinary team care in the management of patients.

Advanced (stage D) heart failure: a statement from the Heart Failure Society of America Guidelines Committee.

We propose that stage D advanced heart failure be defined as the presence of progressive and/or persistent severe signs and symptoms of heart failure despite optimized medical, surgical, and device therapy. Importantly, the progressive decline should be primarily driven by the heart failure syndrome. Formally defining advanced heart failure and specifying when medical and device therapies have failed is challenging, but signs and symptoms, hemodynamics, exercise testing, biomarkers, and risk prediction models are useful in this process. Identification of patients in stage D is a clinically important task because treatments are inherently limited, morbidity is typically progressive, and survival is often short. Age, frailty, and psychosocial issues affect both outcomes and selection of therapy for stage D patients. Heart transplant and mechanical circulatory support devices are potential treatment options in select patients. In addition to considering indications, contraindications, clinical status, and comorbidities, treatment selection for stage D patients involves incorporating the patient's wishes for survival versus quality of life, and palliative and hospice care should be integrated into care plans. More research is needed to determine optimal strategies for patient selection and medical decision making, with the ultimate goal of improving clinical and patient centered outcomes in patients with stage D heart failure.

Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in skeletal muscle.

AIMS: Sphingolipid and oxidant signaling affect glucose uptake, atrophy, and force production of skeletal muscle similarly and both are stimulated by tumor necrosis factor (TNF), suggesting a connection between systems. Sphingolipid signaling is initiated by neutral sphingomyelinase (nSMase), a family of agonist-activated effector enzymes. Northern blot analyses suggest that nSMase3 may be a striated muscle-specific nSMase. The present study tested the hypothesis that nSMase3 protein is expressed in skeletal muscle and functions to regulate TNF-stimulated oxidant production. RESULTS: We demonstrate constitutive nSMase activity in skeletal muscles of healthy mice and humans and in differentiated C2C12 myotubes. nSMase3 (Smpd4 gene) mRNA is highly expressed in muscle. An nSMase3 protein doublet (88 and 85 kD) is derived from alternative mRNA splicing of exon 11. The proteins partition differently. The full-length 88 kD isoform (nSMase3a) fractionates with membrane proteins that are resistant to detergent extraction; the 85 kD isoform lacking exon 11 (nSMase3b) is more readily extracted and fractionates with detergent soluble membrane proteins; neither variant is detected in the cytosol. By immunofluorescence microscopy, nSMase3 resides in both internal and sarcolemmal membranes. Finally, myotube nSMase activity and cytosolic oxidant activity are stimulated by TNF. Both if these responses are inhibited by nSMase3 knockdown. INNOVATION: These findings identify nSMase3 as an intermediate that links TNF receptor activation, sphingolipid signaling, and skeletal muscle oxidant production. CONCLUSION: Our data show that nSMase3 acts as a signaling nSMase in skeletal muscle that is essential for TNF-stimulated oxidant activity.

Transmural heterogeneity of cellular level power output is reduced in human heart failure.

Heart failure is associated with pump dysfunction and remodeling but it is not yet known if the condition affects different transmural regions of the heart in the same way. We tested the hypotheses that the left ventricles of non-failing human hearts exhibit transmural heterogeneity of cellular level contractile properties, and that heart failure produces transmural region-specific changes in contractile function. Permeabilized samples were prepared from the sub-epicardial, mid-myocardial, and sub-endocardial regions of the left ventricular free wall of non-failing (n=6) and failing (n=10) human hearts. Power, an in vitro index of systolic function, was higher in non-failing mid-myocardial samples (0.59±0.06µWmg(-1)) than in samples from the sub-epicardium (p=0.021) and the sub-endocardium (p=0.015). Non-failing mid-myocardial samples also produced more isometric force (14.3±1.33kNm(-2)) than samples from the sub-epicardium (p=0.008) and the sub-endocardium (p=0.026). Heart failure reduced power (p=0.009) and force (p=0.042) but affected the mid-myocardium more than the other transmural regions. Fibrosis increased with heart failure (p=0.021) and mid-myocardial tissue from failing hearts contained more collagen than matched sub-epicardial (p<0.001) and sub-endocardial (p=0.043) samples. Power output was correlated with the relative content of actin and troponin I, and was also statistically linked to the relative content and phosphorylation of desmin and myosin light chain-1. Non-failing human hearts exhibit transmural heterogeneity of contractile properties. In failing organs, region-specific fibrosis produces the greatest contractile deficits in the mid-myocardium. Targeting fibrosis and sarcomeric proteins in the mid-myocardium may be particularly effective therapies for heart failure.