Matthew L. Williams

Cardiac adenoviral S100A1 gene delivery rescues failing myocardium

Cardiac-restricted overexpression of the Ca2+-binding protein S100A1 has been shown to lead to increased myocardial contractile performance in vitro and in vivo. Since decreased cardiac expression of S100A1 is a characteristic of heart failure, we tested the hypothesis that S100A1 gene transfer could restore contractile function of failing myocardium. Adenoviral S100A1 gene delivery normalized S100A1 protein expression in a postinfarction rat heart failure model and reversed contractile dysfunction of failing myocardium in vivo and in vitro. S100A1 gene transfer to failing cardiomyocytes restored diminished intracellular Ca2+ transients and sarcoplasmic reticulum (SR) Ca2+ load mechanistically due to increased SR Ca2+ uptake and reduced SR Ca2+ leak. Moreover, S100A1 gene transfer decreased elevated intracellular Na+ concentrations to levels detected in nonfailing cardiomyocytes, reversed reactivated fetal gene expression, and restored energy supply in failing cardiomyocytes. Intracoronary adenovirus-mediated S100A1 gene delivery in vivo to the postinfarcted failing rat heart normalized myocardial contractile function and Ca2+ handling, which provided support in a physiological context for results found in myocytes. Thus, the present study demonstrates that restoration of S100A1 protein levels in failing myocardium by gene transfer may be a novel therapeutic strategy for the treatment of heart failure.

Targeted β-Adrenergic Receptor Kinase (βARK1) Inhibition by Gene Transfer in Failing Human Hearts

Background—Failing human myocardium is characterized by an attenuated contractile response to &bgr;-adrenergic receptor (&bgr;AR) stimulation due to changes in this signaling cascade, including increased expression and activity of the &bgr;-adrenergic receptor kinase (&bgr;ARK1). This leads to desensitization and downregulation of &bgr;ARs. Previously, expression of a peptide inhibitor of &bgr;ARK1 (&bgr;ARKct) has proven beneficial in several animal models of heart failure (HF). Methods and Results—To test the hypothesis that inhibition of &bgr;ARK1 could improve &bgr;-adrenergic signaling and contractile function in failing human myocytes, the &bgr;ARKct was expressed via adenovirus-mediated (Ad&bgr;ARKct) gene transfer in ventricular myocytes isolated from hearts explanted from 10 patients with end-stage HF undergoing cardiac transplantation. Ad&bgr;ARKct also contained the marker gene, green fluorescent protein, and successful gene transfer was confirmed via fluorescence and immunoblotting. Compared with uninfected failing myocytes (control), the velocities of both contraction and relaxation in the Ad&bgr;ARKct-treated cells were increased in response to the &bgr;-agonist isoproterenol (contraction: 57.5±6.6% versus 37.0±4.2% shortening per second, P <0.05; relaxation: 43.8±5.5% versus 27.5±3.9% lengthening per second, P <0.05). Fractional shortening was similarly enhanced (12.2±1.2% versus 8.0±0.9%, P <0.05). Finally, adenylyl cyclase activity in response to isoproterenol was also increased in Ad&bgr;ARKct-treated myocytes. Conclusions—These results demonstrate that as in animal models of HF, expression of the &bgr;ARKct can improve contractile function and &bgr;-adrenergic responsiveness in failing human myocytes. Thus, &bgr;ARK1 inhibition may represent a therapeutic strategy for human HF.

Impact of Mitral Valve Regurgitation Evaluated by Intraoperative Transesophageal Echocardiography on Long-Term Outcomes After Coronary Artery Bypass Grafting

Background—It is unclear if mild or moderate mitral valve regurgitation (MR) should be repaired at the time of coronary artery bypass grafting (CABG). We sought to determine the long-term effect of uncorrected MR, measured by intraoperative transesophageal echocardiography (TEE), in CABG patients. Methods and Results—Between May 1999 and September 2003, data were gathered for 3264 consecutive patients who underwent isolated CABG and had MR graded by intraoperative TEE. MR was graded on the following 5 levels: none, trace, mild, moderate, and severe. Patients who had severe MR or who underwent mitral valve surgery were eliminated from the analysis. The remaining patients were combined into the following 3 groups: none or trace, mild, and moderate MR. Preoperative and follow-up data were 99% complete. The median length of follow-up was 3.0 years. Multivariable analysis controlling for important preoperative risk factors was performed to determine predictors of death and death/hospitalization for heart failure. Increasing MR was a risk factor for death [hazard ratio (HR), 1.44; P<0.001] and death/heart failure hospitalization (HR, 1.34; P<0.01). When patients with moderate MR were eliminated from the analysis, mild MR was a risk factor for death (HR, 1.34; P=0.011) and death/hospitalization for heart failure (HR, 1.34; P<0.001). Conclusions—Even mild MR, identified by intraoperative TEE, predicts worse outcomes after CABG. Revascularization alone did not eliminate the negative long-term effects of mild MR. CABG patients with uncorrected mild or moderate MR are at increased risk for death and heart-failure hospitalization; consideration for surgical repair or more aggressive medical management and follow-up is warranted.

Survival Prognosis and Surgical Management of Ischemic Mitral Regurgitation

BACKGROUND Ischemic mitral regurgitation (IMR) has an adverse prognosis, but survival characteristics and management are controversial. This study reviewed a 20-year series of IMR patients managed with multiple approaches to assess and refine surgical strategies. METHODS Patients having surgery for primary coronary disease from 1986 to 2006 were divided into group 1 (no IMR; bypass grafting only; n = 16,209), group 2a (IMR; bypass only; n = 3,181), group 2b (IMR; mitral repair; n = 416), and group 2c (IMR; mitral replacement; n = 106). Cox proportional hazards modeling adjusted for baseline differences, and therapeutic adequacy was quantified by area under each survival curve expressed as a percentage of group 1. RESULTS Group 2 patients were older than group 1 patients and had worse baseline characteristics. Group 2a had less severe MR and group 2b had the most comorbidity. Assuming group 1 provided the best adjusted outcome at a given baseline risk, group 2a achieved 97.7%, 2b achieved 93.7%, and 2c achieved 79.1% of potential survival (hazard ratio 1.1, 1.4, and 1.6, respectively; p < 0.003). Most of the survival difference was perioperative. CONCLUSIONS Worse baseline risk is a major factor reducing long-term survival in IMR. Current algorithms in which mild to moderate IMR is managed with bypass only (group 2a) generally produced good late results. In patients with moderate and severe IMR, repair achieved 93.7% of full survival potential; valve replacement was less satisfactory, primarily owing to higher operative mortality. Future therapeutic refinement, emphasizing reparative procedures and better perioperative care, could enhance the surgical prognosis of IMR.

Impact of Tricuspid Valve Regurgitation in Patients Treated With Implantable Left Ventricular Assist Devices

BACKGROUND The progression of tricuspid valve regurgitation (TR) and the impact of preoperative TR on postoperative outcomes in patients having left ventricular assist device (LVAD) implantation has not been studied. METHODS One hundred seventy-six consecutive implantable LVAD procedures were retrospectively reviewed. A total of 137 patients comprised the final study group with complete preimplant characteristics, before and after echocardiogram assessment of TR, and outcomes data. Patients were divided into two groups: insignificant TR (iTR) consisting of those with preimplant TR grades of none, trace, and mild; and significant TR (sTR) consisting of those with moderate and severe TR grades. RESULTS Relative to patients with iTR, patients with sTR were younger (53.6±12.8 versus 58.4±10.0 years, p=0.02) and more commonly had nonischemic cardiomyopathies (69% versus 38%, p<0.001). The preimplant incidence of iTR and sTR was 51% and 49%. Immediately after the LVAD implant procedure, TR did not significantly change. At late follow-up (156±272 days), 32% had moderate or severe TR. Also, 41% of the original sTR group persisted with moderate or severe TR. Relative to patients with iTR, patients with sTR required longer postimplant intravenous inotropic support (8.5 versus 5.0 days, p=0.02), more commonly required a temporary right ventricular assist device, and had a longer postimplant length of hospital stay (27.0 versus 20.0 days, p=0.03). There was also a trend toward decreased survival for sTR versus iTR (log rank=0.05). CONCLUSIONS Tricuspid regurgitation is not reduced immediately after LVAD implantation. Significant TR is associated with longer postimplant inotropic support and length of hospital stay.

Survival on the Heart Transplant Waiting List: Impact of Continuous Flow Left Ventricular Assist Device as Bridge to Transplant

BACKGROUND Continued donor organ shortage and improved outcomes with current left ventricular assist device (LVAD) technology have increased the number of patients supported with bridge-to-transplantation (BTT) therapy. Using the United Network of Organ Sharing (UNOS) database, we assessed the impact on survival in patients supported with BTT while on the heart transplant waiting list. METHODS The UNOS database was queried from January 2005 to June 2012 to identify patients listed for heart transplantation as UNOS status 1A or 1B. Patients implanted with a pulsatile-flow device or an LVAD other than the HeartMate II (HM II; Thoratec Inc, Pleasanton, CA) were excluded. Patients were divided into LVAD and non-LVAD groups based on status at the time of listing. Patients were propensity matched (LVAD -non-LVAD = 1:2) for age, sex, weight, presence of diabetes, creatinine levels, mean pulmonary artery pressure, and UNOS status. Kaplan-Meier curves were analyzed for survival. RESULTS A total of 8,688 patients were analyzed, with 1,504 (17%) in the LVAD group. Average age (52.6 ± 11.8 versus 51.3 ± 12.9 years; p = 0.0002) and weight (86.6 ± 18.6 versus 80.8 ± 18.2 kg; p < 0.0001) at time of listing were higher in the LVAD group. There were more men (79% versus 74%; p < 0.0001) and more patients with diabetes (30% versus 27%; p = 0.03) in the LVAD group. Of all patients, 6,943 patients (80%) underwent transplantation, 862 (10%) died, and 883 (10%) remained on the waiting list. After propensity matching, survival to transplantation was significantly better in the LVAD group than in the non-LVAD group at both 1 year (91% versus 77%) and 2 years (85% versus 68%). CONCLUSIONS Patients supported with an HM II LVAD as BTT therapy were older with increased comorbidities; they demonstrated an improved survival while listed for heart transplantation. The use of LVADs as a BTT strategy can potentially improve patient survival while waiting for transplantation and allow better allocation of donor hearts.

Risk-Adjusted Short- and Long-Term Outcomes for On-Pump Versus Off-Pump Coronary Artery Bypass Surgery

Background—Surgeons have adopted off-pump coronary artery bypass grafting (OPCAB) in an effort to reduce the morbidity of surgical revascularization. However, long-term outcome of OPCAB compared with conventional coronary artery bypass grafting (CABG) remains poorly defined. Methods and Results—Using logistic regression analysis and proportional hazards modeling, short-term and long-term outcomes (perioperative mortality and complications, risk-adjusted survival, and survival/freedom from revascularization) were investigated for patients who underwent OPCAB (641 patients) and CABG-cardiopulmonary bypass (5026 patients) from 1998 to 2003 at our institution. For these variables, follow-up was 98% complete. OPCAB patients were less likely to receive transfusion (odds ratio for OPCAB, 0.80; P=0.037), and there were trends toward improvement in other short-term outcomes compared with CABG-cardiopulmonary bypass. Long-term outcomes analysis demonstrated no difference in survival, but OPCAB patients were more likely to require repeat revascularization (OPCAB hazard ratio, 1.29; P=0.020). Conclusions—OPCAB patients were less likely to receive transfusion during their hospitalization for surgery but had higher risk for revascularization in follow-up. These results highlight the need for a large randomized, controlled trial to compare these 2 techniques.

Mitral Gradients and Frequency of Recurrence of Mitral Regurgitation After Ring Annuloplasty for Ischemic Mitral Regurgitation

BACKGROUND Undersized ring annuloplasty and surgical revascularization are commonly used to correct ischemic mitral regurgitation (MR), but published series have failed to demonstrate a benefit compared with revascularization alone. We hypothesized that surgical revascularization and annuloplasty lead to a durable repair, but may also lead to increased mitral gradients that could limit the benefit of the repair technique. METHODS Data were collected for 222 consecutive patients who underwent combined revascularization and repair for ischemic MR between 1999 and 2006. The most recent transthoracic echocardiogram available for each patient (namely, the study that occurred at the latest date after surgery) was reviewed to define the fate of ischemic MR. When present, the mean gradient across the mitral valve was measured. Cox regression modeling was then performed to determine whether increasing gradients were associated with decreased long-term survival or increased hospitalization for heart failure. RESULTS For the group of 222 patients, echocardiographic follow-up was available for 68% (149 patients). At follow-up, 1.3% had severe MR and 9.4% had moderate MR; 54% of patients (66 of 123) were found to have gradients of 5 mm or greater across the mitral valve, with 11% demonstrating gradients of 8 mm or more. Cox proportional hazards models failed to show adverse effects of increasing mitral gradient on outcomes analyzed: survival hazard ratio = 0.95 (95% confidence interval: 0.82 to 1.11, p = 0.527) and survival/heart failure hospitalization hazard ratio = 1.04 (95% confidence interval: 0.93 to 1.17, p = 0.488). CONCLUSIONS Undersized ring annuloplasty and revascularization can provide a durable correction of ischemic mitral regurgitation. This technique frequently increases the gradient across the mitral valve, but increasing mitral gradient does not appear to adversely impact survival or heart failure hospitalization.

Off-Pump and On-Pump Coronary Revascularization in Patients With Low Ejection Fraction: A Report From The Society of Thoracic Surgeons National Database

BACKGROUND The purpose of this study was to evaluate outcomes of patients with low ejection fraction who underwent surgical coronary revascularization with or without cardiopulmonary bypass (CPB). METHODS The Society of Thoracic Surgeons National Database was queried from January 1, 2008, to June 30, 2011 for patients with an ejection fraction of less than 0.30 who underwent primary, nonemergent coronary artery bypass (CAB) grafting. The entire cohort of 25,667 patients was divided into those who underwent revascularization with (ONCAB, n = 20,509) and without (OPCAB, n = 5,158) CPB. OPCAB patients who were converted to CPB intraoperatively were counted as intended OPCAB and were included in the OPCAB group. Propensity scores were estimated using 32 covariates, and multivariate logistic regression was used to compare risk-adjusted outcomes between groups. RESULTS Patients undergoing planned OPCAB were older, more frequently female, and had a lower body mass index than those who underwent ONCAB. The OPCAB cohort also had higher rates of prior stroke, peripheral vascular disease, and chronic lung disease. The predicted mortality risk was 2.3% for the OPCAB cohort vs 2.1% for the ONCAB group (p < 0.0001). Of the 5,158 patients who underwent OPCAB, unplanned conversion to CPB occurred in 270 (5.2%). OPCAB was associated with significantly lower adjusted risk of death (odds ratio [OR], 0.82), stroke (OR, 0.67), major adverse cardiac events (OR, 0.75), and prolonged intubation (OR, 0.78). Postoperative transfusion rates were significantly lower in the OPCAB group (44.8% vs 51.6%, p < 0.001). There were no adverse outcomes that occurred more commonly in OPCAB patients. The advantage associated with OPCAB was found in the entire Society of Thoracic Surgeons National Database and among high-volume and low-volume OPCAB centers. CONCLUSIONS In The Society of Thoracic Surgeons National Database, OPCAB is associated with significantly reduced adjusted risk of early morbidity and mortality for patients having coronary bypass grafting with an ejection fraction of less than 0.30.

Heart Transplant vs Left Ventricular Assist Device in Heart Transplant-Eligible Patients

BACKGROUND Patients listed for heart transplant have a prolonged wait time, with continued deterioration, poor quality of life, and 10% mortality. Although recent bridge to transplant (BTT) studies demonstrated 1-year survival similar to heart transplantation, doubt remains about overall effectiveness as a treatment strategy compared with waiting and implanting a left ventricular device (LVAD) only as a last resort. We evaluated 1-year outcome and effectiveness of LVAD vs heart transplantation. METHODS Patients on the heart transplantation list, either receiving an allograft or LVAD for BTT from January 2009 to December 2009 were evaluated. Of 43 patients treated, 1 received both LVAD and an allograft during same admission was removed from the analysis. All patients but one who received an allograft had prior LVAD. Descriptive and univariate (t test) statistics and Kaplan-Meier survival curve were used for analyses. RESULTS LVAD for BTT was used in 29 patients (51.4±12.8 years, 6.9% women), and 13 (51.1±11.6 years, 15.38% women) underwent heart transplantation. Initial hospital length of stay was 17.5±14.4 days in BTT group and 14.3±4.6 days in heart transplant group (p=0.44) At 1 year, the total number of days spent in the hospital (operation and related complications), including index hospitalization was 11.6±14.3 days/100 days in BTT and 7.9±9.0 days/100 days in heart transplantation (p=0.38). A total of 41% BTT and 46% heart transplant patients had one readmission within 3 months of the index hospitalization. Infection was the most common cause of readmission in both groups. The 1-year survival was similar for both groups (no hospital death in either group; 3 late deaths in the BTT group). CONCLUSIONS One-year outcomes for patients eligible for heart transplantation were similar whether they received an allograft or LVAD for BTT. Heart transplant outcome for patients with LVAD were not adversely affected. Improving outcomes for patients treated with LVAD suggest that current decision models for patients eligible for heart transplantation may need to be reevaluated.