Sustained release of engineered stromal cell-derived factor 1-α from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction.

BACKGROUND: Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell-derived factor 1-α (engineered stromal cell-derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction. METHODS AND RESULTS: Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical-initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls. CONCLUSIONS: We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.

Quantitative evaluation of change in coexistent mitral regurgitation after aortic valve replacement.

OBJECTIVES: Management of intermediate degrees of mitral regurgitation during aortic valve replacement for aortic stenosis remains controversial. We sought to evaluate the degree of reduction of mitral regurgitation in patients undergoing aortic valve replacement, as well as a mathematical relationship between aortic valve gradient reduction and the degree of mitral regurgitation decrement. METHODS: We retrospectively analyzed demographic, intraoperative, and echocardiographic data on 802 patients who underwent aortic valve replacement or aortic root replacement between January 2010 and March 2011. A total of 578 patients underwent aortic valve replacement or aortic root replacement without intervention on the mitral valve. We excluded 88 patients with severe aortic insufficiency, 3 patients who underwent ventricular assist device placement, 4 patients who underwent prior mitral valve replacement, and 21 patients with incomplete data, yielding 462 patients for analysis. For each patient, the degree of pre- and postoperative mitral regurgitation was graded on a standard 0 to 4+ scale. RESULTS: Of the 462 patients, 289 patients had at least mild mitral regurgitation. On average, mitral regurgitation decreased 0.24 degrees per patient for this cohort of 289 patients. Of the 56 patients with at least moderate mitral regurgitation, mitral regurgitation decreased 0.54 degrees per patient. Of 62 patients who underwent isolated aortic valve replacements, who had at least mild mitral regurgitation, and who had no evidence of structural mitral valve disease, mitral regurgitation decreased 0.24 degrees per patient. Linear regression analysis revealed no relationship between reduction in mitral regurgitation and gradient reduction across the aortic valve. CONCLUSIONS: Reduction in mitral regurgitation after relief of aortic outflow tract obstruction is modest at best. Further, the magnitude of gradient change across the aortic valve has little influence on the degree of reduction in mitral regurgitation. These observations argue at minimum for performing a prospective evaluation of the clinical benefits of addressing moderate mitral regurgitation at the time of aortic valve intervention and may support a more aggressive approach to concomitant mitral surgery.

Rapid onset of fulminant myocarditis portends a favourable prognosis and the ability to bridge mechanical circulatory support to recovery.

OBJECTIVES: Fulminant myocarditis with cardiogenic shock is fatal without mechanical circulatory support. Once haemodynamic stability has been established with a ventricular assist device (VAD), the decision to wait for myocardial recovery as opposed to listing for an orthotopic heart transplant (OHT) can be difficult. We have undertaken this study to establish the criteria for determining the need for heart transplantation following VAD implant for fulminant myocarditis. METHODS: A total of 442 VADs were implanted between 1993 and 2011. Twenty-four VADs were implanted for fulminant myocarditis with refractory cardiogenic shock. We retrospectively analysed the variables and the pathology for this cohort. Patients who had a full recovery of myocardial function and subsequent VAD explant (Explant) were compared with those bridged to OHT. There was one acute death. RESULTS: There was no difference in the past medical history between the groups. Explant patients had a more acute onset of heart failure with a median of 7 days between the onset of symptoms and VAD implant, when compared with 22 days for OHT (P = 0.01). A rapid recovery in myocardial function was seen in the Explant group, with recovery of myocardial function (ejection fraction = 53 ± 24%) in 14 ± 7 days. Myocardial function was sustained for 5 years following the VAD explant. The female gender favoured myocardial recovery and VAD explantability. Two patients had giant cell myocarditis, neither of whom had a recovery of function, and they were bridged to heart transplant with a VAD. CONCLUSIONS: Fulminant myocarditis is a fatal condition without mechanical support. The rapid onset of symptoms is associated with a complete recovery of myocardial function and VAD explant. The absence of rapid recovery of myocardial function should prompt listing for a heart transplant.

Predicting right ventricular failure in the modern, continuous flow left ventricular assist device era.

BACKGROUND: In the era of destination continuous flow left ventricular assist devices (LVAD), the decision of whether a patient will tolerate isolated LVAD support or will need biventricular support (BIVAD) can be challenging. Incorrect decision making with delayed right ventricular (RV) assist device implantation results in increased morbidity and mortality. Continuous flow LVADs have been shown to decrease pulmonary hypertension and improve RV function. We undertook this study to determine predictors in the continuous flow LVAD era that identify patients who are candidates for isolated LVAD therapy as opposed to biventricular support. METHODS: We reviewed demographic, hemodynamic, laboratory, and echocardiographic variables for 218 patients who underwent VAD implant from 2003 through 2011 (LVAD=167, BIVAD=51), during the era of continuous flow LVADs. RESULTS: Fifty preoperative risk factors were compared between patients who were successfully managed with an LVAD and those who required a BIVAD. Seventeen variables demonstrated statistical significance by univariate analysis. Multivariable logistic regression analysis identified central venous pressure>15 mmHg (OR 2.0, "C"), severe RV dysfunction (OR 3.7, "R"), preoperative intubation (OR 4.3, "I"), severe tricuspid regurgitation (OR 4.1, "T"), heart rate>100 (OR 2.0, Tachycardia-"T")-CRITT as the major criteria predictive of the need for biventricular support. Utilizing these data, a highly sensitive and easy to use risk score for determining RV failure was generated that outperformed other established risk stratification tools. CONCLUSIONS: We present a preoperative risk calculator to determine suitability of a patient for isolated LVAD support in the current continuous flow ventricular assist device era.